Brain Advance Access originally published online on January 28, 2004
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Brain, Vol. 127, No. 3, 660-670, 2004
© 2004 Guarantors of Brain
doi: 10.1093/brain/awh073
Forces consistent with plateau-like behaviour of spinal neurons evoked in patients with spinal cord injuries
1 Spinal Injuries Research Centre, Prince of Wales Medical Research Institute and University of New South Wales, 2 College of Health Sciences, University of Sydney, Sydney, Australia and 3 Faculty of Physical Education and Recreation, University of Alberta, Canada
Correspondence to: Dr Peter Nickolls, Prince of Wales Medical Research Institute, Barker St, Randwick, NSW 2031, Australia E-mail: p.nickolls{at}unsw.edu.au
 |
Summary |
|---|
 Top Summary IntroductionMethodsResultsDiscussionReferences |
|---|
Percutaneous electrical stimulation over tibialis anterior and triceps surae was performed in 14 patients with traumatic spinal cord injury (SCI) to look for evidence that ‘extra contractions’ can develop, beyond those due to activation of the motor axons beneath the stimulating electrodes. Criteria for the extra contractions included marked asymmetry of force with respect to stimulation, progressively rising force during stimulation of constant amplitude and frequency, and force remaining high after stimulation frequency had returned to the control level following a high-frequency burst. Twelve of the 14 patients showed evidence of such behaviour, more frequently in triceps surae than tibialis anterior. Force or electromyographic activity commonly outlasted the stimulation in these patients. There was no apparent correlation between the completeness or level of injury and the ability to induce the behaviour. Evidence of force potentiation and ‘habituation’ was also seen. Eleven of the 14 patients exhibited hyper-reflexia and reported spontaneous spasms, but there was no obvious association with the extra contractions. It is concluded that non-classical behaviour of neurons within the spinal cord can contribute to the extra contractions evoked by electrical stimulation over muscles in spinal cord-injured subjects. This central contribution is less easy to obtain than in intact healthy subjects, all of whom showed the phenomenon. These contractions are consistent with the activation of plateau potentials in spinal neurons and, if so, plateau potentials may contribute to a patient’s clinical manifestations.
Key Words: spinal cord injury; plateau potentials; triceps surae; tibialis anterior
Abbreviations: EMG= electromyographic activity; SCI = spinal cord injury; TA = tibialis anterior; TS = triceps surae
Received June 30, 2003. Revised November 2, 2003. Accepted November 9, 2003.
|
Introduction |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionReferences |
|---|
The spinal cord contains complex machinery for the control of movement, and it is now realized that its neurons are involved in multiple functions that depend on circumstances and go far beyond the simple reflexes that were first thought to be the main providence of the cord (McCrea, 1992
). Examples of some simple spinal cord reflexes that may be elicited by artificial stimulation of afferents are the H-reflex, the tonic electrical reflex, the tonic vibration reflex and the flexion reflex. Mechanical vibration applied to the tendon of a skeletal muscle in humans tends to induce an involuntary tonic reflex contraction of this muscle and reciprocal relaxation of its antagonists (De Gail et al., 1966; Eklund and Hagbarth, 1966). Under some conditions, the muscle contraction may continue for 30 s or more after the cessation of the vibration. Similar effects have been observed when electrical stimulation was applied over the tibial nerve in normal man (Lang and Vallbo, 1967). These phenomena are largely mediated by Ia afferents.
Strong stimulation can result in a nociceptive flexion reflex (Dimitrijevi
and Nathan, 1968). In the lower limbs, depending on the site of stimulation, the reflex results in either plantar or dorsiflexion of the toes, dorsiflexion of the ankle and flexion of the knee and hip on the ipsilateral side. There are two components to this response: an early response mediated by A fibres and a late response through C fibres. These reflexes are associated with the perception of pain in intact subjects. They are not stereotyped responses and may be modulated by the movement and position of the limbs (Rossi and Decchi, 1994). Below the pain threshold, cutaneous stimulation in the legs of humans may produce results different from those of stimulation above threshold, and these responses are also modulated by movement and position (e.g. Burke et al., 1991).
In these reflexes, motoneurons may discharge in a linear fashion, with firing frequency proportional to the integrated sum of their inputs (Eccles, 1957; Kernell, 1965; Granit et al., 1966), but, under some circumstances, they may also discharge for prolonged periods outlasting any excitatory inputs (Schwindt and Crill, 1980; for a review see Binder et al., 1993). The latter may occur after activation of muscle spindle afferents by vibration (Hagbarth and Eklund, 1966) or electrical stimulation (e.g. Granit et al., 1957; Hultborn et al., 1975; Wada et al., 1989; Collins et al., 2001). With the long delay between input and response, it was thought originally that polysynaptic reflexes were involved (De Gail et al., 1966; Lang and Vallbo, 1967). However, animal experiments have shown that direct stimulation of motoneurons with injected current can produce bursts of motoneuron action potentials. These discharges last much longer than the original stimulus input, and are superimposed on a long-lasting depolarizing shift in membrane potential termed a ‘plateau potential’ (Hultborn and Kiehn, 1992; Fraser and MacVicar, 1996; Heckman and Lee, 1999; Kiehn et al., 2000; Hultborn et al., 2003; for reviews see Perrier and Hounsgaard, 2000; Hornby et al., 2002; Hounsgaard, 2002). Plateau potentials can also be produced by the application of neurotransmitters or neuromodulators, or indirectly by afferent volleys evoked by vibration, muscle stretch or electrical stimulation in the same manner as the reflexes in humans described above (Bennett et al., 1998a, b; Gorassini et al., 1999). Furthermore, their initiation may take 1 s or more, indicating that a long latency does not necessarily imply transmission through polysynaptic circuits (Genet and Delord, 2002).
In animal experiments, plateau potentials can be induced in spinal neurons by appropriate external stimulation and may occur during coordinated movements, such as walking (Eken and Kiehn, 1989; Brownstone et al., 1992). Plateau potentials in sacral motoneurons have been thought to underlie the spasms that occur with chronic spinal cord injuries (SCIs) in rats (Bennett et al., 2001b). However, there was no evidence of plateau potentials during the acute phase of SCI (Bennett et al., 2001a). Some indirect evidence suggests that plateau potentials may also be induced in able-bodied humans (Kiehn and Eken, 1997; Gorassini et al., 1998, 2002; Collins et al., 2001, 2002; Hornby et al., 2003; Nozaki et al., 2003) and it is thought that they contribute to muscle cramps (Baldissera et al., 1994). Although the mechanisms are not well understood, flexor spasms in patients with chronic SCI can be triggered by noxious and non-noxious skin stimuli, at a lower threshold than for intact subjects, and the reflex electromyographic activity (EMG) can persist after the initial stimulus (e.g. Dimitrijevi and Nathan, 1967, 1968, 1970; Shahani and Young, 1971). Extremes of ankle movement have also been found to trigger flexor spasms in patients with SCI, presumably through group III and IV muscle afferents (Schmit et al., 2000).
The rationale for the present study was to look for evidence that extra contractions thought to be due to ‘plateau-like’ behaviour in spinal neurons can contribute to the contractions evoked by surface stimulation of muscle in patients with SCI, and to assess whether these extra contractions are associated with the spasms and disturbance of tone typical of spinal spasticity.
|
Methods |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionReferences |
|---|
The studies were performed on 14 patients (11 male, three female) with traumatic SCIs. Table 1 shows the clinical details for the patients. The study was repeated on one male after 5 months (patient 7). Five of the 14 patients were deemed to have complete cord sections on clinical grounds, i.e. as well as having no movement they had no residual sensory perception below the lesion. It is still possible to have functioning pathways between the brain and neurons below the lesion in clinically complete cord damage (Bunge et al., 1993
). Two of the incomplete patients were able to produce a force of level 2 on the American Spinal Injury Association scale with their triceps surae (TS) muscles, one incomplete patient produced a force of 1–2 in tibialis anterior (TA), the remainder produced voluntary force in the range 0–1 in the muscles tested. The procedures were approved by the local human research ethics committee, and were performed in accordance with the Declaration of Helsinki. All patients gave informed consent to participate in the study. Patients reclined in a comfortable chair with their hips, knees and ankles flexed to between 90 and 110°. The right foot was strapped to a foot-plate hinged in the same axis as the ankle joint, constrained by a strain-gauge, designed to measure isometric torque developed by the muscles about the ankle joint (Fig. 1).
|
|
Electrical stimulation was applied over both the TS and TA of the right leg through pairs of flexible strip electrodes. For TS, the electrodes were 10–18 cm long and 3.5 cm wide and were positioned across the long axis of the muscle,
10 cm apart, 10 and 20 cm distal to the popliteal fossa. For TA, the electrodes were 5 cm long and 3.5 cm wide and were positioned at right angles to the long axis of TA, 2.5 cm apart, with the proximal electrode 3 cm distal to the tibial tuberosity (Fig. 1).
Trains of five or six pulses, each of 1 ms duration and constant amplitude, were delivered to TA and TS on separate occasions at a rate of 100 Hz by a stimulator (Digitimer DS7), while the force recorded by the strain-gauge attached to the foot-plate was noted. The trains were repeated with increasing stimulus amplitudes until there was no further increase in force. Stimulus amplitude was then adjusted until either the force was 6–10% of the maximal stimulated contraction force for the muscle, or the signal-to-noise ratio of the force was 15 dB (i.e. peak force 6 times the peak noise), whichever was the greater. This stimulus level was similar to that used previously in normal subjects (Collins et al., 2001, 2002) and was chosen to avoid stimulating nociceptors, although the level may have been below that required to produce extra contractions in some patients. If a signal-to-noise ratio of at least 15 dB could not be maintained, further experiments on that muscle were stopped. This occurred for TS in one patient (no. 3). Two additional patients could not be studied because, in spite of stimulus intensities >100 mA for both TS and TA, the forces produced were too small to be distinguishable from the noise. Hyper-reflexia was noted as being present if the patient reported regular spasms at least once per week, if spasms were observed in the patients’ muscles or recorded on the force or EMG traces, or if it was found to be present on clinical examination (Table 1).
Having set stimulus strength as described above, four patterns of stimulation were delivered to each muscle in turn, controlled by a computer using Spike2 software and a ‘1401 plus’ data acquisition interface (Cambridge Electronic Design). All pulses were of 1 ms duration. This pulse width is optimal for ‘central’ contributions to the force generated by repetitive submaximal stimulation (Collins et al., 2002). The four patterns of stimulation (see Fig. 1) were a control train at 25 Hz for 7 s and three patterns of test stimuli. The first test pattern consisted of pulses at frequencies increasing linearly from 4 to 100 Hz over 3 s and then decreasing from 100 Hz to 4 Hz over 3 s (a triangular pattern of stimulation frequency, referred to as ‘triangle’ stimulation). The second test pattern was of 7 s duration and consisted of stimulation at 25 Hz for 2 s, then 100 Hz for 2 s, then 25 Hz for 3 s (referred to as ‘superimposed 100 Hz burst’). The third test pattern consisted of a stimulus train at 100 Hz of variable duration but typically >7 s (referred to as ‘long trains’). Usually five test trains were delivered during each experimental run, with 30–60 s between trains. At the beginning and end of the run, brief trains (5–6 pulses at 100 Hz) were given five times to check the consistency of the patient’s response to stimulation. In some experiments, EMG from TA and TS was recorded using surface electrodes positioned adjacent to those used for stimulation.
Based on previous studies using similar methods, the following criteria were used to indicate that extra, centrally generated contractions had occurred with stimulation (Collins et al., 2001, 2002). With triangle stimulation, there was marked asymmetry in the evoked force such that the forces were relatively larger when stimulus frequency was declining. With the superimposed 100 Hz burst during the 25 Hz train, the force was higher after the 100 Hz burst when compared with the responses evoked by control trains of 25 Hz (of the same duration). In addition, the force was higher after the 100 Hz period than before it. In long trains, force rose after the first 1 s of the tetanus. Force and EMG persisted long (>1 s) after the stimulus trains had been turned off. Each criterion was assessed as being either present or absent, and only one was required for extra contractions to be considered present.
It is known that peripheral nerve dysfunction external to the spinal cord can occur in SCI patients (Nemchausky and Ubilluz, 1995; Rutz et al., 2000). Six patients had motor and sensory studies performed on the median and peroneal nerves. These consisted of conventional nerve conduction studies and needle electromyography, as well as specialized microneurographic and other assessments of nerve excitability and conduction.
Statistical comparisons, between subsets of the patients’ clinical status, and between the responses of patients to different forms of stimulation, were made using either 
2 tests (Fisher’s exact test where appropriate) or Student’s t tests. Student’s t test was performed between patients exhibiting extra contractions and those without to see if there was any relationship to the level of SCI or the time since injury. The significance level was set at 0.05.
|
Results |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionReferences |
|---|
It was possible to induce extra contractions (i.e. contractions in addition to those thought to be generated by direct stimulation of the motor axons) in the majority of patients (12 out of 14) with stimulus strengths greater than or equal to that required to produce 6% of the maximal stimulated contraction force. In such cases, the pattern of evoked force was qualitatively similar to that seen in able-bodied subjects (Collins et al., 2001
, 2002).
Extra contractions
Typical responses of patients with incomplete injuries to stimulation are shown in Fig. 2 (patient 5). The left panels (Fig. 2A) show three patterns of stimulation versus time, with the evoked muscle force above. With ‘triangle’ stimulation (top panel), there was an asymmetry of the force, with greater force as stimulus frequency was decreasing than when it was increasing. With the ‘superimposed 100 Hz burst’ stimulation (middle panels), the force was greater after the 100 Hz burst than before it, even though the stimulus frequency was 25 Hz before and after the burst. The bottom traces show that, during a 7 s train at 100 Hz, the force continued to increase throughout the stimulation. The right panels (Fig. 2B) show the consistency of the response with successive stimuli. The bottom right panels show the forces persisting beyond the end of stimulation.
|
Similar responses were also seen in patients with complete injuries (Fig. 3). The top panels (Fig. 3A) show the response by patient 1 to ‘triangle’ stimulation, showing a similar asymmetry in the force trace to that for the incomplete patients. The bottom panels (Fig. 3B) show the response to ‘superimposed 100 Hz burst’ stimulation for patient 10, with the force after the 100 Hz burst being greater than before it. The right panels again show the consistency of the response with successive stimuli.
|
In one patient (subject 13), successive control trains at 25 Hz for 7 s were followed by 25 Hz stimulation with superimposed bursts at 100 Hz (see Fig. 4). Two control and two test trains were given in each experimental run. Six runs were performed, with the stimulus intensity increasing from 70 mA in the first run, in 10 mA steps to 120 mA in the sixth run. The force immediately after the 100 Hz burst (arrow) differed little from control sequences at 70 mA, but became increasingly greater than control values with higher test currents. This difference reached a maximum with test train currents of 100 mA.
|
Correlation with clinical status
In 12 of the 14 patients, it was possible to induce extra contractions, as defined, using the criteria given in the Methods. Six patients had studies on both TA and TS, seven on TS only, and one on TA only. In seven patients, extra contractions occurred only with TS, in one patient only with TA, and in four patients with both muscle groups. Overall, extra contractions were evoked in 11 out of 13 patients during stimulation over TS and five out of seven during stimulation over TA. In six experiments on the five patients with clinically complete lesions, the incidence of extra contractions showed no relationship to the level of the SCI (Fisher’s exact test, P > 0.05). Similarly there was no significant relationship between the number of patients exhibiting extra contractions and the level of the injury. The stimuli resulted in extra contractions in TS more frequently than in TA (P < 0.05, Table 2, Fisher’s exact test). In all, the 14 patients received 75 triangle stimulations, 54 long train stimulations and 59 superimposed 100 Hz stimulations. No one stimulus pattern was more efficacious, i.e. the type of stimulation did not influence the likelihood of inducing extra contractions.
|
Spasms and extra contractions
Eleven of the 14 patients showed symptoms or signs of hyper-reflexia below the level of injury (Table 1). They reported spontaneous spasms prior to the study, and six were on baclofen to control spasm. There was no significant correlation between hyper-reflexia and the ability to induce extra contractions for either the incomplete or the complete patients, as shown by Fisher’s exact test. During stimulation over TS, some patients developed overt phasic contractions in the antagonist muscle (TA), resulting in the brief dorsiflexion torques shown in Figs 4, 5 and 6. In Fig. 6A (patient 7b), the onset of TS contraction was rapidly followed by a short period of over-riding antagonist contraction (a transient spasm in TA, see also Fig. 5) before the development of the extra contractions in TS. The ‘two-humped’ force profile shown in Fig. 6B (patient 9) evoked during triangular stimulation was typical and probably due to activation of the antagonist in a spasm as the stimulus frequency approached 100 Hz. Alternatively, or in addition, the second ‘hump’ may have been due to a spasm in the agonist.
|
|
Data from one of the three patients who showed no signs of extra contractions, but suffered flexor spasms and had an exaggerated flexion reflex, are shown in Fig. 5 (patient 7a). In this subject, stimulation over both TS (left panels Fig. 5) and TA (not shown) triggered brief spasms in TA. During TS stimulation, as shown in the left panels of Fig. 5, these spasms produced dorsiflexion force (downward deflection) superimposed on plantarflexion force (upward deflection) due to direct TS activation. Panels on the right of Fig. 5 show EMG and force recorded during stimulation of the posterior tibial nerve at the ankle using the same stimulation patterns as used for the TS stimulation. Whether the trains were brief, triangular, superimposed 100 Hz bursts or long trains (successive panels in Fig. 5), posterior tibial stimulation evoked reflex spasms in TA, with dorsiflexion torque profiles similar to those during TS stimulation. Tibial nerve stimulation with six pulses at 100 Hz (top right panel) evoked a TA contraction at a latency of 230 ± 5 ms (SEM n = 7), 180 ms after the last pulse in the train. Figure 5 shows the superimposed force responses to three consecutive stimulus trains. The largest dorsiflexion responses were typically generated by the first in a series of stimulus trains, and successive responses became progressively smaller (i.e. there was habituation, see below).
Figure 6 also shows examples of a potentiation in force (a progressive increase in force with trains repeated at short intervals) and possible ‘habituation’ (Dimitrijevi and Nathan, 1970). The potentation in force bears some similarity to the phenomenon of ‘wind-up’ except that the time constant of action is longer (1–3 min) than in the conventionally defined ‘wind-up’ occurring over 1–2 s (Herrero et al., 2000; see also Gorassini et al., 2002). Figure 6A illustrates responses to five successive triangle trains, separated by intervals of 30–60 s. The force increased with time. In another patient (Fig. 6B; patient 9), force increased from train 1 to 2, but then decreased over the subsequent trains. All patients showed a mixture of habituation and potentiation of their responses. Habituation and potentiation commonly appeared to oscillate during an experimental run, with an approximate period of the oscillation ranging from 80 to 230 s. Overall habituation predominated over potentiation, with the mean drop in peak force being 11.7%, but the standard deviation was large (65.9%). The progressive torque increments in Fig. 6C (patient 6) evoked by consecutive 2 s bursts of 100 Hz stimulation were accompanied by increased EMG in all three components of TS (shown for MG) which continued in LG and MG for 40 s after the final train. The EMG shows two runs of activity during the period of stimulation and a long third run after stimulation ceased, demonstrating that motoneuron firing continued beyond the end of stimulation, as is also clear in the force record. It is possible that one or more of these could have been due to spasm, though the limb was not postured to favour the development of extensor spasms (and spasms would have produced a more phasic EMG pattern). Persistent force or EMG after stimulus trains occurred in 12 of the 14 patients.
Figure 7 shows a recording of a spontaneous spasm in TS and TA in patient 2. It occurred 45 s after a stimulation of TS that did not produce extra contractions (Fig. 7A). Four of the 14 patients had spontaneous spasms during the experiments. 2 analysis revealed no relationship between the presence of spontaneous spasms during the study and extra contractions.
|
Four of the six patients who had peripheral nerve studies had evidence of lower motoneuron or peripheral nerve dysfunction (Table 1). This was evident in those nerves arising below the cord lesion. It was characterized by decreased potentials and high thresholds for excitation, as well as some denervation. When corrected for temperature, there were no significant changes in conduction velocities (V. G. Macefield and M. Kiernan, personal communication). There were no significant correlations with the presence of extra contractions or clinical phenomena.
|
Discussion |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionReferences |
|---|
This study confirms the anecdotal report of Collins et al. (2001
) that, following trains of high-frequency stimuli, extra contractions may be evoked in patients with SCI. These involuntary contractions develop in addition to those due to direct activation of motor axons. The present results show that the magnitude of these extra contractions varies between patients with SCI and that this variability does not depend on whether the lesion is clinically complete or incomplete. Commonly force or EMG persisted after the cessation of stimulation in most patients. Although it is difficult to be certain that a lesion is truly complete on clinical grounds, so that some descending pathways between the brain and spinal cord may still be present in apparently complete SCI, the fact that extra contractions and persistent post-stimulus EMG activity were seen in patients with apparently complete SCI argues against the brain playing an essential role in the generation of these phenomena. There is also evidence that the excitability of the primary motor cortex decreases in normal subjects during sustained muscle contractions, that may be maintained by autonomous activity, thought to be due to plateau-like behaviour of neurons in the human spinal cord (Nozaki et al., 2003).
A possible explanation for the extra contractions is as follows: stimulation over the motor axons causes an initial muscle contraction and activates muscle spindles which initiate action potentials in afferents. The stimulation also directly induces action potentials in afferent fibres. The afferent signals recruit other motoneurons directly and through interneurons and other spinal neurons. This enhances the muscle contraction and gives rise to further feedback to spinal neurons. Initially, the motoneurons would be generating action potentials in a conventional manner, dependent on the sum of their excitatory and inhibitory synaptic inputs. In between action potentials, they would revert to their resting state after the afterhyperpolarization. As the integrated excitatory synaptic input increased, an increasing number of spinal neurons would be driven from their resting state to a plateau-potential state (Genet and Delord, 2002; Hultborn et al., 2003). With further synaptic input, these neurons would respond with sustained burst firing, so further enhancing the muscle contraction. This feedback would continue, with the motoneurons continuing to increase their output even as the stimulation decreased and in some cases continuing to fire after stimulation had ceased. Eventually the neurons would spontaneously revert from their plateau state to their resting state or be driven back to the resting state by inhibitory synaptic input.
In normal healthy people and the incomplete SCI patients, some of the synaptic input giving rise to the plateau state will be from higher centres (Kiehn and Eken, 1997; Gorassini et al., 1998, 2002; Hounsgaard, 2002; for a review see Hornby et al., 2002). The role for plateau potentials is being increasingly recognized in a range of studies in animals and reduced preparations (for reviews see Hounsgaard et al., 1986; Hultborn and Kiehn, 1992; Hornby et al., 2002), and they are likely to be involved in the present findings.
It was possible to evoke these extra contractions in most of the SCI patients (12 out of 14 patients). The stimulation levels may have been too low to evoke the extra contractions in the two patients in whom the phenomenon was not observed. In addition, the presence of peripheral nerve dysfunction could have reduced the phenomenon in some patients. Two additional patients with SCI could not be studied because insufficient force was generated by stimulation over their leg muscles at >100 mA. In contrast, using similar testing methods, all able-bodied subjects examined by Collins et al. (2001, 2002) showed the phenomenon for both TA and TS stimulation. Six patients were tested electrophysiologically for peripheral neuropathy in their lower limbs, as may occur in SCI (Nemchausky and Ubilluz, 1995; Rutz et al., 2000). Evidence for peripheral nerve dysfunction was found in four. Six of the patients were on baclofen at doses designed to reduce spasms, and this drug may have reduced the magnitude and incidence of the extra contractions found in this study. Because of the drug therapy, peripheral neuropathy, the occurrence of spasms in patients, the time-dependent effects produced by stimulation (e.g. habituation) and the difficulty of ensuring identical levels of both afferent and efferent stimulation, it is injudicious to compare directly the amount of torque generated by the central mechanism in able-bodied subjects and those with SCI. However, the results in Figs 2 and 3, for patients with clinically incomplete and complete SCI, bear a qualitative resemblance to those reported in normal subjects (Collins et al., 2002). The size of the force increments was probably less in the patients for the different stimulus trains, though precise comparisons are difficult (see below). In contrast, in chronically spinalized animals, plateau potentials (and presumably the forces they generate) are more common than in intact animals (Bennett et al., 2001a, b). Presumably the difference between the results in spinal animals and humans is due in part to the baclofen therapy and the incidence of peripheral neuropathy (which would reduce afferent input into the cord and motoneuron output). Other causes may be the complete nature of the SCI in animal experiments, compared with the more usual partial injury in humans. This may lead to differences in cord plasticity, synaptic drive to motoneurons and possible effects from partially intact descending spinal cord pathways.
Harnessing this central mechanism to generate extra force by functional electrical stimulation of muscle may afford several advantages over more conventional stimulation techniques that initiate contractions primarily by the synchronous activation of the largest motor axons beneath the stimulating electrodes. The central mechanism activates muscle fibres asynchronously, with the smallest, motor units recruited first (see Collins et al., 2001), and thus, theoretically, the evoked contractions should be more fatigue resistant. It may be easier to evoke contractions of graded strength, and less battery power should be needed. Also, recruitment of muscle fibres that are not normally activated by electrical stimulation may help obviate the muscle atrophy that accompanies chronic SCI. Habituation in this study only caused an 11.7% decrease in force on average, so should not interfere unduly with any clinical application.
In this study, there was a significantly higher incidence of the extra contractions in TS than TA. This may be due to the higher proportion of small motoneurons innervating TS (associated with type I muscle fibres), particularly soleus. These motoneurons have a greater susceptibility to develop plateau-like behaviour (Lee and Heckman, 1998, 2000). However such a difference was not apparent in able-bodied subjects (Collins et al., 2002). It is possible that disruption of descending systems is more pronounced for flexor than extensor muscles after SCI. Such a loss could reduce the total excitatory synaptic input to the motoneurons, thus rendering them less likely to be driven into a plateau state.
In the present study, the level and completeness of the lesion and the time since injury had no significant effect on the incidence of the extra contractions. This could reflect the relatively small study population. We estimate that a sample size in excess of 50 may be required to assess these correlations with more certainty. It is difficult to evoke the tonic vibration reflex in patients with spinal cord lesions (Hagbarth and Eklund, 1968; Burke et al., 1972), a finding which suggests that the central mechanism for generation of extra forces is less obvious in these patients. All patients in this study sustained their injury at least 3 months prior to undergoing their study. Plateau-like phenomena are seen in chronic but not acute spinal rats (Bennett et al., 2001b). A factor complicating the interpretation of clinical data is medication. Extra forces induced by stimulation could not be demonstrated in patients 7a, 12 and 14 who were all on routine medication, including baclofen, but were clinically hyper-reflexic despite this medication.
Figure 6 illustrates other effects that have been reported previously for normal subjects and patients with SCI. In addition to the extra contractions, force potentiation and habituation were also seen (see also Fig. 5). Extra contractions are qualitatively similar to the ‘wind-up’ of force observed over a few seconds that is a feature of plateau potentials in motoneurons studied in animal preparations (Bennett et al., 1998b; Herrero et al., 2000; see also Hornby et al., 2003). However, the force potentiation occurred over a period of minutes, rather than seconds. Due to the long duration of the stimulation trains used in this study (6–7 s), any such wind-up during a stimulation train would contribute to the extra contractions. Other factors with a longer time course may also be involved. The force potentiation over a longer period than that of wind-up, demonstrated in this study, could be due to integration with a longer time constant of excitatory effects in spinal circuits.
Stimulation of the posterior tibial nerve resulted in a flexion reflex with similar characteristics to the antagonist contractions recorded in the same subjects during the muscle stimulation over TS (see Fig. 5). Such reflexes are larger in SCI than in the able-bodied population and typically habituate quickly (Shahani and Young, 1971). The extra contractions seen in this study may be due to a wind-up phenomenon occurring during the long stimulation trains and appear distinct from the flexion reflex contractions. Contractions due to plateau activation in animal studies tend to increase with repeated stimulations due to the wind-up described above (Bennett et al., 1998b; Herrero et al., 2000). Thus one interpretation of the data is that the extra contractions include a component due to plateau-like behaviour and that the flexion reflexes are a different phenomenon. However, flexion reflexes in humans recently have been linked with plateau phenomena (Hornby et al., 2003).
This study has shown formally that surface stimulation over lower limb muscles following spinal cord injury can produce unexpected force increments that vary in size but that can be dissociated from obvious hyper-reflexia. Persistent motoneuron firing after stimulation occurred in most (12 out of 14) patients, and this has been observed with similar inputs in able-bodied subjects (Collins et al., 2001, 2002; Nozaki et al., 2003) and after voluntary contractions in thenar muscles of patients with cervical lesions of the spinal cord (Zijdewind and Thomas, 2003). The probable mechanism of action is afferent feedback, coupled with feedback circuits within the spinal cord, leading to a large synaptic input into neurons driving them into a plateau state that in turn gives rise to motoneuronal firing. The mechanism is likely to be contained within the spinal cord, as demonstrated by the appearance of the phenomenon in patients with clinically complete spinal cord lesions.
|
Acknowledgements |
|---|
We wish to thank Drs Stella Engel and Leanne Hunt of the Prince of Wales and Prince Henry Hospitals, Sydney for their assistance in recruiting subjects for the studies. This work was supported by the National Health and Medical Research Council of Australia (3206) and the Alberta Heritage Foundation for Medical Research (DFC).
|
References |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionReferences |
|---|
Baldissera F, Cavallari P, Dworzak F. Motor neuron ‘bistability’. A pathogenetic mechanism for cramps and myokymia. Brain 1994; 117: 929–39.
Bennett DJ, Hultborn H, Fedirchuk B, Gorassini M. Synaptic activation of plateaus in hindlimb motoneurons of decerebrate cats. J Neurophysiol 1998a; 80: 2023–37.
Bennett DJ, Hultborn H, Fedirchuk B, Gorassini M. Short-term plasticity in hindlimb motoneurons of decerebrate cats. J Neurophysiol 1998b; 80: 2038–45.
Bennett DJ, Li Y, Siu M. Plateau potentials in sacrocaudal motoneurons of chronic spinal rats, recorded in vitro. J Neurophysiol 2001a; 86: 1955–71.
Bennett DJ, Li Y, Harvey PJ, Gorassini M. Evidence for plateau potentials in tail motoneurons of awake chronic spinal rats with spasticity. J Neurophysiol 2001b; 86: 1972–82.
Binder MD, Heckman CJ, Powers RK. How different afferent inputs control motoneuron discharge and the output of the motoneuron pool. Curr Opin Neurobiol 1993; 3: 1028–34.[CrossRef][Medline]
Brownstone RM, Jordan LM, Kriellaars DJ, Noga BR, Shefchyk SJ. On the regulation of repetitive firing in lumbar motoneurones during fictive locomotion in the cat. Exp Brain Res 1992; 90: 441–55.[Web of Science][Medline]
Bunge RP, Puckett WR, Becerra JL, Marcillo A, Quencer RM. Observations on the pathology of human spinal cord injury. A review and classification of 22 new cases with details from a case of chronic cord compression with extensive focal demyelination. Adv Neurol 1993; 59: 75–89.[Medline]
Burke D, Andrews CJ, Lance JW. Tonic vibration reflex in spasticity, Parkinson’s disease, and normal subjects. J Neurol Neurosurg Psychiatry 1972; 35: 477–86.
Burke D, Dickson HG, Skuse NF. Task-dependent changes in the responses to low-threshold cutaneous afferent volleys in the human lower limb. J Physiol 1991; 432: 445–58.
Collins DF, Burke D, Gandevia SC. Large involuntary forces consistent with plateau-like behavior of human motoneurons. J Neurosci 2001; 21: 4059–65.
Collins DF, Burke D, Gandevia SC. Sustained contractions produced by plateau-like behaviour in human motoneurones. J Physiol 2002; 538: 289–301.
De Gail P, Lance JW, Neilson PD. Differential effects on tonic and phasic reflex mechanisms produced by vibration of muscles in man. J Neurol Neurosurg Psychiatry 1966; 29: 1–11.
Dimitrijevi MR, Nathan PW. Studies of spasticity in man. I. Some features of spasticity. Brain 1967; 90: 1–30.
Dimitrijevi MR, Nathan PW. Studies of spasticity in man. 3. Analysis of reflex activity evoked by noxious cutaneous stimulation. Brain 1968; 91: 349–68.
Dimitrijevi MR, Nathan PW. Studies of spasticity in man. 4. Changes in flexion reflex with repetitive cutaneous stimulation in spinal man. Brain 1970; 93: 743–68.
Eccles JC. The physiology of nerve cells. Baltimore: John Hopkins University Press; 1957.
Eken T, Kiehn O. Bistable firing properties of soleus motor units in unrestrained rats. Acta Physiol Scand 1989; 136: 383–94.[Web of Science][Medline]
Eklund G, Hagbarth K-E. Normal variability of tonic vibration reflexes in man. Exp Neurol 1966; 16: 80–92.[CrossRef][Web of Science][Medline]
Fraser DD, MacVicar BA. Cholinergic-dependent plateau potential in hippocampal CA1 pyramidal neurons. J Neurosci 1996; 16: 4113–28.
Genet S, Delord B. A biophysical model of nonlinear dynamics underlying plateau potentials and calcium spikes in Purkinje cell dendrites. J Neurophysiol 2002; 88: 2430–44.
Gorassini M, Bennett DJ, Yang JF. Self-sustained firing of human motor units. Neurosci Lett 1998; 247: 13–6.[CrossRef][Web of Science][Medline]
Gorassini M, Bennett DJ, Kiehn O, Eken T, Hultborn H. Activation patterns of hindlimb motor units in the awake rat and their relation to motoneuron intrinsic properties. J Neurophysiol 1999; 82: 709–17.
Gorassini M, Yang JF, Siu M, Bennett DJ. Intrinsic activation of human motoneurons: possible contribution to motor unit excitation. J Neurophysiol 2002; 87: 1850–8.
Granit R, Phillips CG, Skoglund S, Steg G. Differentiation of tonic from phasic alpha ventral horn cells by stretch, pinna and crossed extensor reflexes. J Neurophysiol 1957; 20: 470–81.
Granit R, Kernell D, Lamarre Y. Algebraical summation in synaptic activation of motoneurons firing within the ‘primary range’ to injected currents. J Physiol 1966; 187: 379–99.
Hagbarth K-E, Eklund G. Motor effects of vibratory muscle stimuli in man. In: Granit R, editor. Muscular afferents and motor control. Proceedings of the First Nobel Symposium; 1965 June; Södergarn, Stockholm, Sweden. Stockholm: Almqvist and Wiksell; 1966. p. 177–86.
Hagbarth K-E, Eklund G. The effects of muscle vibration in spasticity, rigidity, and cerebellar disorders. J Neurol Neurosurg Psychiatry 1968; 31: 207–13.
Heckman CJ, Lee RH. The role of voltage-sensitive dendritic conductances in generating bistable firing patterns in motoneurons. J Physiol Paris 1999; 93: 97–100.[CrossRef][Web of Science][Medline]
Herrero JF, Laird JMA, Lopez-Garcia JA. Wind-up of spinal cord neurones and pain sensation: much ado about something? Prog Neurobiol 2000; 61: 169–203.[CrossRef][Web of Science][Medline]
Hornby TG, McDonagh JC, Reinking RM, Stuart DG. Motoneurons: a preferred firing range across vertebrate species? Muscle Nerve 2002; 25: 632–48.[CrossRef][Web of Science][Medline]
Hornby TG, Rymer WZ, Benz EN, Schmit BD. Windup of flexion reflexes in chronic human spinal cord injury: a marker for neuronal plateau potentials? J Neurophysiol 2003; 89: 416–26.
Hounsgaard J. Motoneurons do what motoneurons have to do. J Physiol 2002; 538: 4.
Hounsgaard J, Hultborn H, Kiehn O. Transmitter-controlled properties of alpha-motoneurones causing long-lasting motor discharge to brief excitatory inputs. Prog Brain Res 1986; 64: 39–49.[Web of Science][Medline]
Hultborn H, Kiehn O. Neuromodulation of vertebrate motoneurone membrane properties. Curr Opin Neurobiol 1992; 2: 770–5.[CrossRef][Medline]
Hultborn H, Wigström H, Wängberg B. Prolonged activation of soleus motoneurons following a conditioning train in soleus Ia afferents—a case for a reverberating loop? Neurosci Lett 1975; 1: 147–52.[CrossRef][Web of Science]
Hultborn H, Denton ME, Wienecke J, Nielsen JB. Variable amplification of synaptic input to cat spinal motoneurones by dendritic persistent inward current. J Physiol 2003; 552: 945–52.
Kernell D. The adaptation and the relation between discharge frequency and current strength of cat lumbosacral motoneurons stimulated by long-lasting injected currents. Acta Physiol Scand 1965; 65: 65–73.[Web of Science]
Kiehn O, Eken T. Prolonged firing in motor units: evidence of plateau potentials in human motoneurons? J Neurophysiol 1997; 78: 3061–8.
Kiehn O, Kjaerulff O, Tresch MC, Harris-Warrick RM. Contributions of intrinsic motor neuron properties to the production of rhythmic motor output in the mammalian spinal cord. Brain Res Bull 2000; 53: 649–59.[CrossRef][Web of Science][Medline]
Lang AH, Vallbo ÅB. Motoneuron activation by low intensity tetanic stimulation of muscle afferents in man. Exp Neurol 1967; 18: 383–91.[CrossRef][Web of Science][Medline]
Lee RH, Heckman CJ. Bistability in spinal motoneurons in vivo: systematic variations in rhythmic firing patterns. J Neurophysiol 1998; 80: 572–82.
Lee RH, Heckman CJ. Adjustable amplification of synaptic input in the dendrites of spinal motoneurons in vivo. J Neurosci 2000; 20: 6734–40.
McCrea DA. Can sense be made of spinal interneuron circuits? Behav Brain Sci 1992; 15: 633–43.[Web of Science]
Nemchausky BA, Ubilluz RM. Upper extremity neuropathies in patients with spinal cord injuries. J Spinal Cord Med 1995; 18: 95–7.[Medline]
Nozaki D, Kawashima N, Aramaki Y, Akai M, Nakazawa K, Nakajima Y, et al. Sustained muscle contractions maintained by autonomous neuronal activity within the human spinal cord. J Neurophysiol 2003; 90: 2090–7.
Perrier J-F, Hounsgaard J. Development and regulation of response properties in spinal cord motoneurons. Brain Res Bull 2000; 53: 529–35.[CrossRef][Web of Science][Medline]
Rossi A, Decchi B. Flexibility of lower limb reflex responses to painful cutaneous stimulation in standing humans: evidence of load-dependent modulation. J Physiol 1994; 481: 521–32.
Rutz S, Dietz V, Curt A. Diagnostic and prognostic value of compound motor action potential of lower limbs in acute paraplegic patients. Spinal Cord 2000; 38: 203–10.[CrossRef][Web of Science][Medline]
Schmit BD, McKenna-Cole A, Rymer WZ. Flexor reflexes in chronic spinal cord injury triggered by imposed ankle rotation. Muscle Nerve 2000; 23: 793–803.[CrossRef][Web of Science][Medline]
Schwindt P, Crill W. Role of a persistent inward current in motoneuron bursting during spinal seizures. J Neurophysiol 1980; 43: 1296–318.
Shahani BT, Young RR. Human flexor reflexes. J Neurol Neurosurg Psychiatry 1971; 34: 616–27.
Wada N, Nakajima Y, Homma S. Long-lasting afterdischarge of alpha-motoneurons after muscle vibration or electrical stimulation of group I afferent fibers in the anemically decerebrated cat. Neurosci Res 1989; 6: 234–7.[CrossRef][Web of Science][Medline]
Zijdewind I, Thomas CK. Motor unit firing during and after voluntary contractions of human thenar muscles weakened by spinal cord injury. J Neurophysiol 2003; 89: 2065–71.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  O. Lagerquist, L. D. Walsh, J.-S. Blouin, D. F. Collins, and S. C. Gandevia Effect of a peripheral nerve block on torque produced by repetitive electrical stimulation J Appl Physiol, July 1, 2009; 107(1): 161 - 167. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-S. Blouin, L. D. Walsh, P. Nickolls, and S. C. Gandevia High-frequency submaximal stimulation over muscle evokes centrally generated forces in human upper limb skeletal muscles J Appl Physiol, February 1, 2009; 106(2): 370 - 377. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. K. Powers "Extra" force evoked by percutaneous muscle stimulation: mechanisms and potential therapeutic applications J Appl Physiol, February 1, 2009; 106(2): 353 - 355. [Full Text] [PDF]
|
|
|
|
 |
|
 J. G. McPherson, M. D. Ellis, C. J. Heckman, and J. P. A. Dewald Evidence for Increased Activation of Persistent Inward Currents in Individuals With Chronic Hemiparetic Stroke J Neurophysiol, December 1, 2008; 100(6): 3236 - 3243. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.J. Heckman, M. Johnson, C. Mottram, and J. Schuster Persistent Inward Currents in Spinal Motoneurons and Their Influence on Human Motoneuron Firing Patterns Neuroscientist, June 1, 2008; 14(3): 264 - 275. [Abstract] [PDF]
|
|
|
|
 |
|
 J. A. Norton, D. J. Bennett, M. E. Knash, K. C. Murray, and M. A. Gorassini Changes in sensory-evoked synaptic activation of motoneurons after spinal cord injury in man Brain, June 1, 2008; 131(6): 1478 - 1491. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. A. Riley, A. H. Maerz, J. C. Litsey, and R. M. Enoka Motor unit recruitment in human biceps brachii during sustained voluntary contractions J. Physiol., April 15, 2008; 586(8): 2183 - 2193. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Dean, L. M. Yates, and D. F. Collins Turning on the central contribution to contractions evoked by neuromuscular electrical stimulation J Appl Physiol, July 1, 2007; 103(1): 170 - 176. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. K. Jankelowitz, J. Howells, and D. Burke Plasticity of inwardly rectifying conductances following a corticospinal lesion in human subjects J. Physiol., June 15, 2007; 581(3): 927 - 940. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M. Klakowicz, E. R. L. Baldwin, and D. F. Collins Contribution of M-Waves and H-Reflexes to Contractions Evoked by Tetanic Nerve Stimulation in Humans J Neurophysiol, September 1, 2006; 96(3): 1293 - 1302. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. R. L. Baldwin, P. M. Klakowicz, and D. F. Collins Wide-pulse-width, high-frequency neuromuscular stimulation: implications for functional electrical stimulation J Appl Physiol, July 1, 2006; 101(1): 228 - 240. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. G. Hornby, J. H. Kahn, M. Wu, and B. D. Schmit Temporal facilitation of spastic stretch reflexes following human spinal cord injury J. Physiol., March 15, 2006; 571(3): 593 - 604. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. K. Floeter, P. Zhai, R. Saigal, Y. Kim, and J. Statland Motor Neuron Firing Dysfunction in Spastic Patients With Primary Lateral Sclerosis J Neurophysiol, August 1, 2005; 94(2): 919 - 927. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A J Thompson, L Jarrett, L Lockley, J Marsden, and V L Stevenson Clinical management of spasticity J. Neurol. Neurosurg. Psychiatry, April 1, 2005; 76(4): 459 - 463. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||