Brain, Vol. 123, No. 8, 1688-1702,
August 2000
© 2000 Oxford University Press
Presynaptic inhibition and homosynaptic depression
A comparison between lower and upper limbs in normal human subjects and patients with hemiplegia
Laboratoire de Neurophysiologie Clinique, Rééducation, Hôpital de la Salpétrière,Paris, France
Correspondence to:
Rose Katz, Rééducation, Hôpital de la Salpêtrière, 47 boulevard de l'Hôpital, F-75651 Paris cedex 13, France E-mail: rose.katz{at}psl.ap-hop-paris.fr
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Abstract |
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Presynaptic inhibition of Ia terminals and postactivation depression at the Ia fibre–motor neuron (MN) synapses were compared in the upper and lower limbs of both sides in subjects from different populations: 49 spastic patients with hemiplegia [mainly with a lesion in the middle cerebral artery (MCA) area], two tetraplegics and 35 healthy subjects. Presynaptic inhibition was assessed using D1 inhibition of the soleus and the flexor carpi radialis (FCR) H reflexes elicited by electrical stimuli applied to the nerve supplying antagonistic muscles, and postactivation depression was explored by varying the time interval between two consecutive H reflexes. In normal subjects no right–left asymmetry was found in the amount of presynaptic Ia inhibition, homosynaptic depression or the Hmax/Mmax ratio. In the hemiplegic side of patients with MCA area lesions, the Hmax/Mmax ratio was significantly increased in the soleus but not in the FCR. Presynaptic inhibition of Ia terminals, which was significantly reduced at the cervical level on the hemiplegic side (and also, but to a lesser extent, on the unaffected side), was unchanged at the lumbar level. Homosynaptic depression was similarly reduced at the cervical and lumbar levels on the hemiplegic side but not modified on the unaffected side. It is argued that the decrease in presynaptic inhibition of Ia terminals is more a correlate of spasticity than a mechanism underlying it. The decrease in postactivation depression, which very probably contributes to the exaggeration of the stretch reflex characterizing spasticity, might be a consequence of the changes in the pattern of activation of Ia afferents and MNs following the motor impairment.
spasticity; presynaptic inhibition; hemiplegia; homosynaptic depression; lower and upper limbs
ACA = anterior cerebral artery; CPN = common peroneal nerve; FCR = flexor carpi radialis; MCA = middle cerebral artery; MN = motor neuron; PAD = primary afferent depolarization
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Introduction |
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Many spinal pathways control the excitability of the stretch reflex and a malfunction in any one of them could theoretically produce an exaggeration of the stretch reflex (for references, see Pierrot-Deseilligny, 1990; Dietz, 1992). Methods are now available to selectively investigate spinal pathways in humans, and these have been used to explore various spinal mechanisms underlying spasticity. Thus, abnormalities of transmission in various postsynaptic pathways have been revealed: decreased Ib inhibition in hemiplegics (Delwaide and Olivier, 1988), reduced Renshaw inhibition in patients with progressive paraparesis (Mazzochio and Rossi, 1997) and abnormalities in reciprocal Ia inhibition in patients with spinal cord lesions (Boorman et al., 1991
; Crone et al., 1994) and with hemiplegia (Nakashima et al., 1989; Artieda et al., 1991). It has also been claimed that a decrease in presynaptic inhibition of Ia terminals is present in most spastic patients (Delwaide, 1971, 1973; Ashby et al., 1980).
In the cat, presynaptic inhibition of Ia terminals, accompanied by primary afferent depolarization (PAD) and caused by axo-axonal GABAA-ergic synapses, may substantially reduce the monosynaptic transmission of Ia excitatory effects (Rudomin, 1990). Because presynaptic inhibition is intimately related to PAD, which is probably one of its underlying mechanisms (for references, see Jankowska, 1992), and in order to differentiate it from postactivation depression, it will be referred as `presynaptic inhibition with PAD' in this paper. Decreased presynaptic inhibition of Ia terminals might cause exaggeration of the stretch reflex, as it has been argued that, in normal subjects, under resting conditions, there is a tonic presynaptic inhibition of Ia terminals (Hultborn et al., 1987b). The argument used in favour of decreased presynaptic inhibition of Ia terminals in spastics was the decrease in the depression of the H reflex induced by tonic vibration applied to the homonymous tendon found in these patients. Indeed, since this depression is seen along with a motor discharge (the tonic vibration reflex), indicating increased excitability of the motor neurons (MNs), it must reflect a presynaptic mechanism. It has been postulated (Delwaide, 1973) and generally accepted (Koelmann et al., 1993) that this mechanism is presynaptic inhibition with PAD. However, when the conditioning vibration is applied on the homonymous tendon, the postactivation depression evoked by repetitive synaptic activation (Katz et al., 1977; Crone and Nielsen, 1989; Hultborn et al., 1996) also contributes to the vibration-induced depression of the reflex. The problem is serious as it has been shown that this homosynaptic depression, probably related to a reduced probability of transmitter release (Lev-Tov and Pinco, 1992), is decreased in spastic patients (Nielsen et al., 1995). These two depressions also differ in their time course, which lasts only 400 ms at the most for presynaptic inhibition with PAD but several seconds (up to 10–15 s) for postactivation depression (Crone and Nielsen, 1989; Nielsen et al., 1995). The first aim of this investigation was to explore the relative contributions of these two mechanisms to the malfunction of the monosynaptic reflex arc in the same patients.
So far, only a few experiments have investigated changes in the presynaptic inhibition of Ia terminals in the upper limb of spastic patients. Using radial-induced inhibition (the equivalent of the D1 inhibition described in the soleus by Mizuno et al., 1971) of the flexor carpi radialis (FCR) H reflex (Berardelli et al., 1987), Nakashima and colleagues (Nakashima et al., 1989) and Artieda and colleagues (Artieda et al., 1991) have found that presynaptic inhibition of Ia terminals projecting to FCR MNs is reduced in the affected arm of patients with hemiplegia. This seems to contradict the absence of changes in presynaptic inhibition of Ia terminals found in the lower limb of hemiplegics by Faist and colleagues (Faist et al., 1994). However, since a different method was used in that study [heteronymous facilitation of the Sol H reflex (Hultborn et al., 1987a)], the second aim of the present investigation was to perform, in the same patients, a comparative study of presynaptic inhibition with PAD in the upper and lower limbs while using similar techniques to estimate it.
Finally, it has been shown that abnormalities in transmission in spinal pathways may also be found on the apparently unaffected side of patients with hemiplegia in both the lower (Castaigne et al., 1966; Pierrot-Deseilligny et al., 1973; Thilmann et al., 1993) and the upper limb (Thilmann et al., 1990). The amount of presynaptic inhibition with PAD and that of homosynaptic depression was thus compared in the same subjects (normals and patients) between left and right sides and between upper and lower limbs, for each configuration (right and left upper limbs; right and left lower limbs).
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Subjects and methods |
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Subjects
The investigation was carried out in 35 normal subjects aged 19–53 years (mean and SEM 36 ± 1.74 years), 32 of whom were right-handed [17 having a laterality coefficient of +100%, calculated using the Edinburgh handedness inventory (Oldfield, 1971
)], and in 51 patients with a CNS lesion, aged 28–77 years (mean and SEM 49.52 ± 1.73 years), all but one of whom were right-handed. All gave informed consent to the procedure, which was approved by the ethical committee of the CCPPRB, Paris Pitié-Salpétrière Hôpital. Subject consent was obtained according to the Declaration of Helsinki.
Forty-nine patients had a unilateral focal cerebral lesion visualized on computed tomography or MRI of the brain: 44 of the lesions were in the area of the middle cerebral artery (MCA) and the patient had spasticity and motor impairment predominantly in the upper limb; five lesions were in the area of the anterior cerebral artery (ACA) and the patient had spasticity and motor impairment that spared (totally or almost totally) the upper limb. Forty-one patients had suffered from ischaemia and eight from a haemorrhage. In addition, two patients with a traumatic spinal cord lesion at C5–C6 level, resulting in incomplete and approximately symmetrical tetraplegia with exaggerated tendon reflexes in both upper limbs, were studied. At the time of the investigation, the duration of the illness varied from 2 months to 19 years. For patients who were taking a myorelaxant drug, the treatment was not interrupted at the time of the investigation. Details of the 51 patients and of the 35 normal subjects examined in this study are summarized in Tables 1 and 2.
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General experimental arrangement
The subjects were seated comfortably in an armchair. The leg that was to be examined was fixed loosely with the hip semi-flexed (120°), the knee slightly flexed (160°) and the ankle at 110°. The forearm and hand to be examined were lying in pronation on the arm of the chair with the shoulder abducted at ~60°and the elbow semi-flexed.
H reflexes
The H reflexes elicited in the wrist and finger flexors (referred to as the FCR H reflex) and in the soleus (Sol), which are regularly found in normal subjects, were chosen as test reflexes in the upper and lower limbs. The surface EMG was recorded from pairs of non-polarizable discs (0.9 cm diameter) placed 1.5 cm apart over the bellies of the corresponding muscles. Percutaneous electrical stimuli (rectangular shocks of 1 ms duration every 4 s) were applied to the median nerve through bipolar electrodes placed just above the elbow and to the posterior tibial nerve through a monopolar electrode (the active electrode being in the popliteal fossa). Amplitudes of H reflexes (peak to peak) were analysed with a computer and expressed as the mean ± 1 SEM.
Hmax/Mmax ratio
The Hmax/Mmax ratio was assessed in the four configurations (left and right FCR and Sol) in 17 normal subjects and 20 patients. The frequency of stimulation was 0.25 Hz.
Amplitude of the unconditioned reflexes
The sensitivity of the H reflex to facilitation or inhibition can vary with the size of the unconditioned reflex, since, at low reflex amplitudes, it increases with increasing size of the unconditioned reflex (Crone et al., 1990). The first step was thus to adjust the amplitude of the unconditioned test reflex (as a percentage of Mmax) so that it was of similar magnitude on both sides and in each subject (normal and patients), and within the range where the sensitivity to inhibition no longer increases with the size of the unconditioned reflex (Crone et al., 1990).
Some patients (32 out of 51) were reluctant to accept the unpleasant feeling accompanying the strong electrical stimulation giving rise to Mmax. However, in these cases, the similarity of the Hmax/Mmax ratio in the FCR of normal subjects and patients and the constant sensitivity of the H reflex to D1 inhibition (used to assess presynaptic inhibition of Ia terminals) within the range over which the unconditioned test reflex amplitude (around Hmax/2) was varied (see Results) allowed us to take into account results that were not related to Mmax.
Method of assessing presynaptic inhibition (with PAD) of Ia terminals
Principle of the method
Presynaptic inhibition of Ia terminals mediating the afferent volley of the test H reflex (FCR and Sol) was evoked by electrical stimuli applied to the nerve supplying antagonistic muscles (Fig. 1A). The resulting reflex depression (Fig. 1B), the amount of which depends on the excitability of PAD interneurons, was assessed: the larger this excitability, the larger the presynaptic inhibition of the test afferent volley and thus the reflex depression [the so-called D1 inhibition (Mizuno et al., 1971)]. Electrical stimulation of the radial nerve elicits in the FCR H reflex, after the initial disynaptic reciprocal Ia inhibition, a second depression which occurs when the interstimulus interval is 5–50 ms (Day et al., 1984). Because, at interstimulus intervals of 10–20 ms, the same conditioning volley does not modify the cortical-evoked response in the FCR, the radial-induced depression of the reflex may be attributed to presynaptic inhibition of the Ia terminals mediating the afferent volley of the FCR H reflex (Berardelli et al., 1987). Similarly, Mizuno and colleagues (Mizuno et al., 1971) have shown that electrical stimulation of the common peroneal nerve (CPN) evokes in Sol MNs an early and short-lasting disynaptic reciprocal Ia inhibition followed by a long-lasting (D1) inhibition, which has been shown not to be paralleled by a depression of the cortically evoked response in Sol MNs (Faist et al., 1996).
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Conditioning stimuli
Conditioning stimuli were electrical stimuli applied percutaneously through bipolar electrodes. The radial nerve was stimulated a few centimetres above the elbow (shocks of 1 ms duration, intensity 0.95 times the motor threshold, the interval between test and conditioning stimuli being 13 ms). In the lower limb, the CPN was stimulated at the caput fibulae. Since the D1 inhibition of the Sol H reflex is more regularly found when the conditioning stimulus is a train of few shocks (Mizuno et al., 1971
; El-Tohamy and Sedgwick, 1983), the conditioning stimulation was a train of three shocks (300 Hz, 1 ms duration, 1.2 times the motor threshold, the interval between the first shock of the train and the test stimulus being 21 ms). At this interstimulus interval, the monosynaptic Ia excitation evoked by stimulation of Ia afferents from peroneal muscles in Sol MNs (Meunier et al., 1993), which may obscure the disynaptic reciprocal Ia inhibition (Petersen et al., 1998), has vanished.
Organization of the experiments
Two runs of 40 stimulations were performed for each configuration (both sides in the upper and lower limbs of each subject). In each run, 20 control and conditioned H reflexes were presented randomly. The amplitude of the conditioned test reflex was expressed as a percentage of its unconditioned value, thus representing the value (mean ± 1 SEM) to which the control reflex was reduced by presynaptic inhibition with PAD.
Method of assessing homosynaptic depression
It has long been observed that the amplitude of the monosynaptic reflex in the cat (Lloyd and Wilson, 1957) and man (Magladery et al., 1952; Paillard, 1955) decreases during repetitive stimulation. The reflex depression is very dramatic at short intervals (1–2 s) and then decreases progressively, even though this attenuation requires at least 10 s to vanish completely (Crone and Nielsen, 1989). In the present study (Fig. 1B
), the interval between two consecutive reflexes (in the FCR or the Sol) was varied between 1 and 12 s. The intensity was adjusted so that the amplitude of the reflexes evoked every 3 s was equal to Hmax/2 (i.e. 15–25 and 25–35% of Mmax for the FCR and Sol H reflexes, respectively), and we verified that the amplitude of the reflex evoked every 3 s remained constant throughout the experiment. In order to compare statistically the results among the different configurations (both sides within the different populations, and differences between the populations), the ratio of the H reflex amplitude evoked every 2 s to the H reflex amplitude evoked every 8 s (referred to as the 2 s/8 s ratio in the following) was calculated in each case.
Statistical analysis
Statistical comparisons between the different configurations (both sides within the different populations, and differences between the populations) and possible correlations between electrophysiological results and clinical features were made using non-parametric tests (Wilcoxon, Mann–Whitney, Spearman and Kolmogorov–Smirnov tests) for both presynaptic inhibition with PAD and homosynaptic depression.
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Results |
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Normal subjects
Hmax/Mmax ratio
The Hmax/Mmax ratio was assessed for each configuration in 17 normal subjects, all but one of whom were right-handed. No statistical difference was found between the mean values observed between right and left sides either in the FCR (34.2 ± 5.4 versus 30.8 ± 5, P = 0.75) or in the Sol (47.5 ± 5 versus 48.8 ± 5.1, P = 0.80). To compare the Hmax/Mmax ratio between patients and normal subjects, the mean values of (left + right) Hmax/Mmax ratios were calculated in normal subjects for both FCR (32.5 ± 4.7%) and Sol (48.2 ± 4.5%). The finding that the Hmax/Mmax ratio was smaller in the FCR than in the Sol (P < 0.02) may be related to the fact that the Hmax response in the FCR was generally obtained with a stimulation that also elicited a direct M response, the resulting antidromic motor volley evoking recurrent inhibition that prevents the discharge of late-recruited MNs in the H reflex (see Discussion).
Inhibition of H reflexes induced by stimulation of radial and common peroneal nerves
Radial-induced depression of the FCR and CPN-induced depression of the Sol H reflexes are shown in Fig. 2A and B, respectively; the value to which the H reflex was reduced by the conditioning stimulation is expressed as a percentage of the control reflex value, and in each graph in Fig. 2A and B comparison is made between the results obtained on the right and left sides (each thin oblique line corresponds to one subject). Mean values obtained on each side are indicated beside each vertical line and are represented on it (filled circles and thick line). As stated in Subjects and methods, unconditioned test reflexes, expressed as a percentage of Mmax, were adjusted to have about the same amplitude. Mean values of radial- and CPN-induced depressions of the FCR and Sol H reflexes were almost symmetrical (right 55.6 ± 4.9, left 51.7 ± 4.9% for the FCR, 13 subjects, P = 0.55; right 63.9 ± 4.9, left 65.9 ± 4.3% for the Sol, 15 subjects, P = 0.49), the absence of asymmetry also being found when considering the individual values in Fig. 2A and B.
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Because Mmax was not assessed in all patients (see Subjects and methods), two kinds of control experiment were performed to ensure that similar results were obtained when the size of the control reflex was related not to Mmax but to Hmax/2.
- (i) We checked that the sensitivity of the H reflexes to radial- and CPN-induced depression remained constant when the control reflex amplitude (expressed as a percentage of Mmax (Crone et al., 1990) was varied within the range of 5–20% of Mmax for the FCR (seven subjects) and 10–30% of Mmax for the Sol (11 subjects).
- (ii) We checked that similar results were obtained when the amplitude of the control H reflex was set at Hmax/2. Thus, in Fig. 2C and D
, which are arranged as Fig. 2A and B, the radial-induced depression of the FCR (Fig. 2C, 26 subjects) and the CPN-induced depression of the Sol (Fig. 2D, 32 subjects) H reflexes are shown when the unconditioned reflex amplitude was set at Hmax/2 (corresponding to ~15 and ~25% of Mmax for the FCR and Sol, respectively, in those subjects in whom Mmax was assessed). The mean values indicated beside each vertical line are very similar to those of Fig. 2A and B, and here again the amount of D1 inhibition of the H reflex compared between the two sides at the cervical and lumbar levels was very symmetrical in a sample of normal subjects who were almost all right-handed (similar results were obtained when only the right-handed subjects with a laterality coefficient of +100% were considered).
- (ii) We checked that similar results were obtained when the amplitude of the control H reflex was set at Hmax/2. Thus, in Fig. 2C and D
Homosynaptic depression
FCR H reflex.
Figure 3A illustrates the results obtained in nine normal subjects when the interval between two consecutive FCR H reflexes was varied from 1 to 12 s. The reflex amplitude increased when the test stimulus frequency (expressed in seconds between reflexes) decreased. At a test stimulus interval of 12 s the reflex size did not increase further and was used as the reference value (i.e. 100%). For interstimulus intervals of <8 s, the amplitude of the reflex decreased rapidly, as described by Crone and Nielsen for the Sol H reflex (Crone and Nielsen, 1989). Here again, there was no asymmetry and the time course of the homosynaptic depression of the FCR H reflex was very similar on the right and left sides (hatched and open columns, respectively).
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Comparison in the upper and lower limb.
Figure 3B
shows that the time courses of the homosynaptic depression of the FCR (hatched columns) and Sol (open columns) H reflexes (right + left) are almost identical.
Ratio 2 s/8 s.
To allow statistical comparison between normal subjects and patients, the 2 s/8 s ratio (see Patients and methods) was calculated in 19 normal subjects (the amplitude of the unconditioned test reflex being adjusted at the 3 s interval at 15–18 and 23–25% of Mmax for the FCR and the Sol, respectively). Figure 3C and D (arranged as in Fig. 2) show that very similar and symmetrical results were obtained in the upper and lower limbs (right 59.9 ± 3.6, left 55.9 ± 3.6% for the FCR; right 61.9 ± 3.9, left 59.9 ± 3.2% for the Sol).
Patients
Hmax/Mmax ratio
The Hmax/Mmax ratio was assessed in 20 hemiplegic patients for both the FCR and the Sol reflex. In the FCR, the mean value of the Hmax/Mmax ratio was 36.9 ± 5% on the hemiplegic side and 34.3 ± 5.8% on the unaffected side, i.e. very close to and not statistically different from the value obtained in normal subjects (32.5%). In contrast, in the Sol, the mean value on the hemiplegic side (63.5 ± 6.7%) was significantly (P < 0.01) higher than on the unaffected side (48.1 ± 7.5%), which was very close to the value found in normal subjects (48.2%).
Radial-induced depression of the FCR H reflex
In Fig. 4A and C (arranged as Fig. 2A and C) the radial-induced depression of the FCR H reflex is compared between the affected and unaffected sides of patients with lesions in the MCA area and thus motor abnormalities at wrist level. Figure 4A shows the results obtained in the 12 patients in whom Mmax was assessed and the amplitude of the unconditioned reflex adjusted to be within the same range as in normal subjects. The mean radial-induced depression of the FCR H reflex was significantly smaller on the hemiplegic side, where the test reflex was reduced to only 81.62% of its control value, than on the unaffected side (69.93%, P < 0.004) and in normal subjects (53.7%, P < 0.002). The radial-induced depression found on the unaffected side of these patients was also significantly reduced (P < 0.02) with respect to normal subjects (Fig. 5).
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In 32 patients, the unconditioned FCR test reflex amplitude was set at Hmax/2. This was possible because, as seen above, (i) the sensitivity to D1 inhibition of the FCR H reflex was not modified when the unconditioned test reflex amplitude varied within the range 5–20% of Mmax; and (ii) there was no statistical difference between the FCR Hmax/Mmax ratios of patients and normal subjects. Figure 4C
shows that the mean values so obtained were very similar to those found in the experiments in which the control H reflex was related to Mmax (Fig. 4A): 83.78 and 68.71% on the patients' hemiplegic and unaffected sides, respectively, versus 58.6% in normal subjects, each value in the patients differing highly significantly from the value in normal subjects (P < 0.01).
Individual results in Fig. 4A and C show that the amount of radial-induced depression was reduced in almost all these patients with respect to the mean value observed in normal subjects (horizontal dotted line), whether the unconditioned H reflex value was related to Mmax (Fig. 4A) or set at Hmax/2 (Fig. 4C). Despite the significant reduction in the radial-induced depression found on the unaffected side of the patients, individual results in Fig. 4C also show that asymmetry, with smaller depression in the hemiplegic side, was observed in almost all (28 out of 32) patients.
The results obtained in the five patients with lesions in the area of the ACA, in whom motor abnormalities at wrist level were either absent or very slight, show that the radial-induced depression of the FCR H reflex, although it was less marked than in normal subjects, on average, was symmetrical (Table 3A) on the two sides. In the two tetraplegic patients (Table 3B) the radial-induced depression of the FCR H reflexes had disappeared almost completely on both sides.
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Depression of the soleus H reflex by stimulation of CPN
Figure 4B
shows that there was no consistent difference in CPN-induced depression of the Sol H reflex between the affected (71.9%) and unaffected (75.5%) sides of 11 patients with lesions in the MCA area, in whom the amplitude of the unconditioned reflex (expressed as a percentage of Mmax) was adjusted to be within the same range as in normal subjects. In the five patients with lesions in the ACA area, despite major motor impairment of the lower limb, the CPN-induced depression of the Sol H reflex found on the affected and unaffected sides (75.6 and 72.3%, respectively) was on average very close to that found in patients with a lesion in the area of the MCA.
In Fig. 5 a comparison is made between the mean values of the reduction by the D1 inhibition of the Sol and FCR H reflexes on the hemiplegic and unaffected sides of patients with lesions in the MCA area and in normal subjects. Even though the reduction of the Sol H reflex by D1 inhibition was slightly smaller on both sides of hemiplegic patients than that observed in normal subjects, the difference did not reach statistical significance, contrary to what was observed for the FCR H reflex.
Homosynaptic depression
The experiments were performed in 16 patients having a lesion in the area of the MCA. In Fig. 6 a comparison is made between the mean values of results obtained on the hemiplegic side of four patients and in seven normal subjects as the interval between two consecutive FCR H reflexes varied from 2 to 12 s. In the hemiplegic side of the patients, the frequency-induced depression was less pronounced and its duration was shorter than that observed in normal subjects. The results closely resemble those described by Nielsen and colleagues in patients with spinal cord injury (Nielsen et al., 1995).
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To allow comparison between normal subjects and patients, the 2 s/8 s ratio (see Subjects and methods) was calculated for the FCR and Sol H reflexes. The amplitude of the reflexes was adjusted at Hmax/2, i.e. within the range 14–22% of Mmax for the FCR and 22–33% for the Sol, when the interval between two consecutive reflexes was 3 s. Mean values of the 2 s/8 s ratio (Fig. 7A
) show that, contrary to the D1 inhibition (Fig. 5), the reduction of the H reflex by the homosynaptic depression was significantly less marked in both the upper and the lower limb of the hemiplegic side (FCR, 84.7%; Sol, 78.3%) when compared with either the unaffected side (65.02 and 62.82%, P < 0.07; individual results in Fig. 7B and C showed that the asymmetry occurred in almost all patients) or normal subjects (57.8 and 60.1%, P < 0.004). The differences between the unaffected side of the patients and the normal subjects was far from reaching statistical significance (P > 0.30).
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Discussion |
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Whereas there was no asymmetry between the two sides in normal subjects for the three parameters studied in the present investigation, these parameters were modified differently in the population of hemiplegic patients with a lesion in the area of the MCA: (i) the Hmax/Mmax ratio was increased on the hemiplegic side in the Sol but not in the FCR; (ii) the radial-induced depression of the FCR H reflex was reduced on the hemiplegic side and, to a lesser extent, on the unaffected side, whereas the CPN-induced depression of the Sol H reflex was not modified; (iii) the homosynaptic depression of both the FCR and Sol H reflexes was reduced on the hemiplegic side but not on the unaffected side.
Absence of asymmetry in normal subjects
Despite the asymmetry (with larger monosynaptic and polysynaptic reflexes on the right side) seen in control rats and cats by Hultborn and Malmsten (1983a, b), the present investigation shows that there is no side asymmetry in man in (i) the Hmax/Mmax ratio, (ii) the homosynaptic depression of the H reflex, or (iii) the amount of D1 inhibition of the H reflex.
The absence of asymmetry in the radial-induced depression of the FCR H reflex, which was also found when we considered only subjects with frank handedness (see Results), confirms previous results (Artieda et al., 1991). In fact, evidence for side asymmetry in the human cervical spinal cord has been obtained only in investigations of non-segmental pathways: thus, handedness-related asymmetry in favour of the dominant side has been found in (i) the transmission of the non-monosynaptic excitation to ECR (extensor carpi radialis) MNs via premotor neurons located rostrally with respect to MNs (Marchand-Pauvert et al., 1999), and (ii) the excitability of the recovery cycle of the FCR H reflex (Tan, 1989), which involves several spinal and supraspinal pathways. Conflicting results have been reported for the recovery cycle of the Sol H reflex, with asymmetry not related to handedness (Goode et al., 1980), in favour of the left side whatever the dominant side (Nativ et al., 1989), or in favour of the non-dominant side (Tan, 1984).
Presynaptic inhibition with PAD
Differential effect on presynaptic inhibition of FCR and Sol Ia terminals
Validity of the method used to estimate presynaptic inhibition.
Because conditioning volleys eliciting the late and long-lasting D1 inhibition of the H reflex do not depress the MEP evoked by cortical stimulation in the FCR (Berardelli et al., 1987) and in the Sol (Faist et al., 1996), this reflex depression has been attributed to presynaptic inhibition of Ia terminals mediating the afferent volley of the test reflex (postsynaptic inhibition should elicit parallel suppression of H and cortical-evoked responses). Recent experiments (Meunier and Pierrot-Deseilligny, 1998) investigating the cortical control of presynaptic inhibition have confirmed the reliability of the D1 method in estimating the excitability of PAD interneurons, as congruent results were obtained with this method and with methods relying on an entirely different principle [heteronymous facilitation of the H reflex (Hultborn et al., 1987a); assessment of the peak of monosynaptic Ia excitation in PSTH experiments (Katz et al., 1988)].
Lower limb.
The absence of any significant changes in the D1 inhibition of the Sol H reflex in patients with hemiplegia (Figs 4B and 5) therefore suggests that, compared with normal subjects, patients with hemiplegia do not show modification of presynaptic inhibition of Ia fibres directed to Sol MNs in either the affected or the unaffected lower limb. A similar result has been found by Faist and colleagues (Faist et al., 1994), who used the heteronymous facilitation of the H reflex (Hultborn et al., 1987a) to assess presynaptic inhibition of Ia terminals in the lower limb. It is of interest that this absence of evidence for changes in presynaptic inhibition of Sol Ia afferents was also found in patients who had predominant motor impairment accompanied by marked spasticity in the lower limb after a lesion in the area of the ACA (Table 3A).
Upper limb.
The reduction in the D1 inhibition of the FCR H reflex in the affected side of patients with hemiplegia has been described previously (Nakashima et al., 1989; Artieda et al., 1991). The present results, which were obtained in a greater number of patients (32) and are very consistent within the population of patients (Fig. 4B), fully confirm that presynaptic inhibition of FCR Ia terminals is depressed on the affected side of patients with hemiplegia due to a lesion in the area of the MCA, i.e. a lesion that has injured the part of the corticospinal tract controlling the upper limb. Accordingly, a spinal lesion of the corticospinal tract above the FCR motor nucleus almost completely abolished presynaptic inhibition of FCR Ia terminals in the two paraplegics with a C5–C6 lesion (Table 3B).
An alternative explanation for the decrease in radial-induced inhibition is a difference in the effect of the corticospinal lesion on low- and high-threshold MNs producing a widening of the usual range of functional thresholds within the MN pool and thereby a decrease in the input–output relation of the test reflex. Even though a contribution from such a change in the recruitment gain of the reflex (Kernell and Hultborn, 1990) cannot be excluded completely, it appears very unlikely, since (i) if anything, one would expect that the enhanced reflex activity seen in spasticity to be accompanied by an increase in the recruitment gain of the reflex (Nielsen and Hultborn, 1993); (ii) a decrease in the recruitment gain of the reflex should also have depressed the Hmax/Mmax ratio with respect to normal subjects (which was not the case: the ratio was 36.9% in patients and 32.5% in normal subjects).
Mechanisms underlying changes in presynaptic inhibition of Ia terminals
In the cat hindlimb, the dominant corticospinal effect on PAD interneurons projecting on Ia afferents is depression (Lundberg and Vyklicky, 1963), which masks an opposite facilitatory effect (Hongo et al., 1972). One of the main findings in the present investigation is that, in the same patients, presynaptic inhibition of Ia terminals was found to be depressed in the upper limb but not in the lower limb. The simplest explanation for this differential effect is the normal opposite control exerted by the motor cortex on PAD interneurons in the lower and upper limbs, with TMS (transcranial magnetic stimulation)-induced depression of presynaptic inhibition of Sol Ia terminals but dominant TMS-induced facilitation of presynaptic inhibition of FCR Ia terminals (Meunier and Pierrot-Deseilligny, 1998). Note, however, that the TMS-induced facilitation of presynaptic inhibition of FCR Ia terminals can be easily reversed to depression in the presence of a cutaneous stimulation (S. Meunier, personal communication).
If the normal cortical control of PAD interneurons discussed above is exerted tonically, the loss of this effect after a corticospinal lesion would be expected to produce a decrease in the presynaptic inhibition of FCR Ia terminals and increased presynaptic inhibition of Sol Ia terminals. In fact, although the former was found consistently, the latter was not observed. This might reflect the normal tonic facilitatory cortical control of PAD interneurons in the cervical spinal cord, whereas the depressive cortical control of PAD interneurons in the lumbar spinal cord, which is revealed at the onset of voluntary contraction (Hultborn et al., 1987b), is not exerted tonically. It may be pointed out that this cortical-induced depression of presynaptic inhibition at the onset of voluntary contraction also exists in the upper limb (Burke et al., 1992): actually, in both limbs it seems to be advantageous to increase the gain of the monosynaptic stretch reflex in the involved muscle at the onset of contraction (Meunier and Pierrot-Deseilligny, 1989). Thus, although similar descending control of PAD interneurons is observed at the onset of voluntary contraction in both limbs, the present results suggest that, in the absence of movement, the organization of the cortical control of presynaptic inhibition in the upper and lower limbs differs not only in its polarity (dominant facilitation versus depression) but also in its character (tonic or not tonic).
Other important differences exist in the organization of lumbar and cervical pathways. In the lumbar enlargement, the widely distributed pattern of heteronymous monosynaptic Ia excitation (Meunier et al., 1993) and the dominant peripheral facilitation of lumbar premotor neurons co-activated by group I and group II afferents (Simonetta-Moreau et al., 1999) seem to be appropriate to the provision of the reflex assistance required by bipedal stance and gait. In contrast, in the upper limb, which has been freed from postural tasks, heteronymous monosynaptic Ia excitation is restricted to projections from distal to proximal muscles (Cavallari et al., 1992; Marchand-Pauvert et al., 2000) and pathways seem to have evolved to optimize the inhibitory mechanisms favouring the focus of the descending command: thus the cortically induced facilitation of PAD interneurons (see above) might work together with the dominant inhibition by peripheral afferents of premotor neurons mediating disynaptic corticospinal excitation of MNs (Pierrot-Deseilligny, 1996).
Changes in presynaptic inhibition and spasticity
Several arguments suggest that the changes in presynaptic inhibition of FCR Ia terminals observed in the present investigation are a simple correlate of the brain lesion without real influence on the degree of spasticity or on the motor command impairment.
- (i) Although the Achilles tendon jerk was exaggerated on the affected side of most patients, there was no evidence for decreased D1 inhibition of the Sol H reflex, even in patients with a lesion in the area of the ACA.
- (ii) Although presynaptic inhibition of FCR Ia afferents was decreased on the affected side of patients with hemiplegia after a lesion in the area of the MCA, there was no correlation between this decrease in presynaptic inhibition and the presence or absence of spasticity (P > 28) or the degree of motor command impairment (P = 0.11) at wrist level.
- (iii) Presynaptic inhibition of FCR Ia afferents was also reduced, although to a lesser extent, on the `unaffected' side. This is not surprising, given that, as stated in the Introduction, abnormalities in transmission in spinal pathways revealed by electrophysiological methods are not rare in the apparently unaffected side of patients with hemiplegia; motor paresis has also been reported in the `unaffected' upper limb, reflecting ipsilateral corticofugal projections and/or synaptic reorganization following stroke (Gandevia, 1993
). It remains true, however, that this decrease in presynaptic inhibition of FCR Ia terminals was observed in the absence of any significant spasticity and motor impairment at the wrist or digit level.
- (iv) Given that the H reflex is more sensitive to presynaptic inhibition of Ia afferents than the stretch reflex and the tendon jerk (Morita et al., 1997
), the decrease in presynaptic inhibition of FCR Ia afferents should have increased the H reflex to a greater extent than the stretch reflex. On the contrary, despite the stretch reflex exaggeration of wrist and finger flexors observed in most patients, the Hmax/Mmax ratio was not significantly higher than in normal subjects, on average.
- (v) Nakashima and colleagues have shown that the presynaptic phase of reciprocal inhibition between forearm muscles is also reduced in patients with movement disorders other than spasticity, such as occupational cramps and symptomatic hemidystonia (Nakashima et al., 1989
). This favours the hypothesis that changes in presynaptic inhibition are a non-specific correlate of motor abnormality.
- (ii) Although presynaptic inhibition of FCR Ia afferents was decreased on the affected side of patients with hemiplegia after a lesion in the area of the MCA, there was no correlation between this decrease in presynaptic inhibition and the presence or absence of spasticity (P > 28) or the degree of motor command impairment (P = 0.11) at wrist level.
Homosynaptic depression
The present investigation confirms and extends the results obtained with the Sol H reflex in normal subjects (Crone and Nielsen, 1989) and in patients with spinal cord lesions (Nielsen et al., 1993, 1995). Indeed, it is shown here that the postactivation depression, assessed as the frequency-related depression of the H reflex, is (i) symmetrical on both sides in normal subjects, and very similar in the FCR and the Sol, and (ii) similarly depressed on the affected side of patients at cervical and lumbar levels, but not depressed on their unaffected side (Fig. 7A). Thus, as in patients with paraplegia or multiple sclerosis (Nielsen et al., 1993; 1995), reduced postactivation depression might contribute to the spasticity observed on the affected side of patients with hemiplegia.
Postactivation depression is due to reduced release of transmitter from previously activated fibres (Hultborn et al., 1996). As emphasized by Hultborn and Nielsen (1998), the decreased depression seen in patients with a lesion of the CNS does not necessarily imply that postactivation depression is under direct control from descending pathways. A more likely explanation is the development of adaptive changes in the efficiency of the Ia–MN synapse following the changes in activity of MNs and Ia fibres resulting from the impairment of the motor command. The fact that spasticity progresses during the weeks or months after stroke fits this hypothesis, since such adaptive changes require time to develop. The finding that, contrary to other electrophysiological changes so far explored (see Introduction and above), the postactivation depression is unchanged on the unaffected side of patients with hemiplegia is also consistent with the adaptive changes related to the motor impairment of the affected side.
Hmax/Mmax ratio
Because the Hmax/Mmax ratio was explored with a stimulation frequency of 0.25 Hz, i.e. a frequency at which the frequency-related depression of the H reflex due to homosynaptic depression has not vanished in normal subjects, the decrease in homosynaptic depression in patients could contribute to the increase in the Hmax/Mmax ratio observed in the Sol [and well known in the literature (Yanagisawa et al., 1993)]. However, although the homosynaptic depression was depressed similarly at the cervical level (Fig. 7A), the Hmax/Mmax ratio was hardly increased at all in the FCR. This might indicate that the mechanisms tending to increase the FCR H reflex (decrease both in presynaptic inhibition of Ia afferents and in postactivation depression) are counteracted by an inhibitory mechanism limiting the size of the FCR H reflex. It has been shown that, because of the rise time of the compound monosynaptic test Ia EPSP (excitatory postsynaptic potential), there is ample time for a disynaptic IPSP (inhibitory postsynaptic potential) to suppress the spike in the last motor neurons contributing to the test reflex discharge (Burke et al., 1984). In this connection, disynaptic recurrent inhibition could be a good candidate, because (i) recurrent inhibition is often increased in patients with hemiplegia with regard to normal subjects (Katz and Pierrot-Deseilligny, 1982) or to the unaffected side (Chaco et al., 1984) [in this respect, intercollicular decerebration in the cat has also been shown to facilitate recurrent inhibition (Benecke et al., 1974)]; and (ii) in the FCR, contrary to the Sol, the Hmax response was generally obtained with a stimulation that also elicited a direct M response. Thus, recurrent inhibition elicited by both the discharge of early orthodromically recruited MNs and by the antidromic volley due to direct stimulation of motor axons (and in addition centrally facilitated or disinhibited with respect to normal subjects) would oppose the recruitment of late-recruited MNs and limit the size of the Hmax. This increased recurrent inhibition might also contribute to the limitation of the size of Hmax in the Sol, although to a lesser extent than in the FCR, because of the absence of an antidromic motor volley elicited by the test stimulus.
In conclusion, contrary to the opinion generally accepted during the 1970s and 1980s, the present investigation confirms that in hemiplegic patients, a decrease in presynaptic inhibition does not exist in Sol Ia terminals, and shows that, although a decrease in presynaptic inhibition is present in FCR Ia afferents, it does not contribute significantly to the spasticity of wrist flexors. Postactivation depression, which was found to be reduced in both the Sol and the FCR on the affected side, might account at least partly for the exaggeration of the stretch reflex.
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Acknowledgments |
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The authors wish to express their gratitude to L. Mazières and Professor E. Pierrot-Deseilligny for reading and commenting upon the manuscript, to F. Mentre and A. Mallet for help for the statistical analysis and to M. Dodo and A. Rigaudie for excellent technical assistance. This work was supported by grants from Assistance Publique-Hôpitaux de Paris (AP-HP, PHRC 95 038), Institut National de la Santé et de la Recherche Médicale (INSERM, CRI 9611), Ministère de l'Enseignement Supérieur et de la Recherche (EA 2393) and Institut pour la Recherche sur la Moelle Epinière (IRME).
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Received November 8, 1999. Revised March 2, 2000. Accepted March 21, 2000.
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