Motor unit firing pattern, synchrony and coherence in a deafferented patient.

The firing of spinal motoneurons (MNs) is controlled continuously by inputs from muscle, joint and skin receptors. Besides altering MN synaptic drive, the removal of these inputs is liable to alter the synaptic noise and, thus, the variability of their tonic activity. Sensory afferents, which are a major source of common and/or synchronized inputs shared by several MNs, may also contribute to the coupling in the time and frequency domains (synchrony and coherence, respectively) observed when cross-correlation and coherence analyses are applied to the discharges of MN pairs. Surprisingly, no consistent changes in firing frequency, nor in synchrony and coherence were reported to affect the activity of 3 pairs of motor units (MUs) tested in a case of sensory polyradiculoneuropathy (SPRNP), leading to an irreversible loss of large diameter sensory afferents (Farmer et al., 1993). Such a limited sample, however, precludes a definite conclusion about the actual impact that a chronic loss of muscle and cutaneous afferents may have on the firing properties of human MUs. To address this issue, the firing pattern of 92 MU pairs was analyzed at low contraction force in a case of SPRNP leading similarly to a permanent loss of proprioceptive inputs. Compared with 8 control subjects, MNs in this patient tended to discharge with slightly shorter inter-spike intervals but with greater variability. Synchronous firing tended to occur more frequently with a tighter coupling in the patient. There was no consistent change in coherence in the 15-30 Hz frequency range attributed to the MN corticospinal drive, but a greater coherence was observed below 5 Hz and between 30 and 60 Hz in the patient. The possible origins of the greater irregularity in MN tonic discharges, the tighter coupling of the synchronous firing and the changes in coherence observed in the absence of proprioceptive inputs are discussed.

Reliability of EMG determinism to detect changes in motor unit synchrony and coherence during submaximal contraction.

The determinism (DET) is a parameter used in nonlinear analysis to quantify the occurrence of recurrent patterns in a signal. Applied to the electromyographic activity (EMG), DET has been proposed as an index of motor unit synchrony in human. We have recently shown that the amount of motor unit synchronous firings above chance level was enhanced with stronger submaximal muscle contraction. Using these data, we aimed at determining if (1) EMG DET and motor unit synchrony varied in the same way and (2) EMG DET was more specifically related to the degree of oscillatory coupling between motor unit discharges. Cross-correlation and coherence analyses were applied to the discharges of 30 motor unit pairs tested at various force levels to assess the amount of synchronous impulses and the strength of oscillatory coupling in the time and frequency domains, respectively. Recurrent quantification analysis was applied to EMG activity to extract its DET. Overall, changes in EMG DET were poorly explained by changes in motor unit synchronous impulse probability (6%) and frequency (5%), and by changes in motor unit coherence in the 6-12Hz (5%) and 25-40Hz (8%) bands. Moreover, the comparison of the data obtained at the weakest and the strongest contraction levels tested with each motor unit pair showed that EMG DET remained unaltered with stronger contraction despite the occurrence of consistent changes in motor unit synchrony in both time and frequency domains. This speaks strongly against the reliability of DET in evaluating changes in motor unit synchronization during submaximal muscle contraction.

Influence of contraction strength on single motor unit synchronous activity.

OBJECTIVE: The influence of contraction strength on motoneurone (MN) synchrony is poorly documented. With stronger contraction, more common and/or synchronized inputs might contribute to greater MN drive and generate more synchronous firings. This effect might be counterbalanced, however, by a negative impact of MN faster firing rates on synaptic effectiveness. METHODS: Pairs of motor units (MUs) were tested at various force levels, in 2-s sequences. MN synchrony was assessed using the index k', the synchronous impulse probability (SIP), and the synchronous impulse frequency (SIF) in cross-correlograms. MU inter-spike interval duration and variability, surface EMG activity and force output were evaluated concurrently. RESULTS: Both SIP and SIF increased with contraction strength, whereas k' remained unaffected. Faster firing rates and stronger contraction had the greatest effects on SIF. CONCLUSIONS: By testing the same MUs at different force levels, we showed that contraction strength does influence MN synchrony. The enhancement of MU synchrony with stronger contraction suggests an efficient contribution of more common and/or synchronized inputs. SIGNIFICANCE: Force output must be controlled when assessing MN synchrony. Normalizing MU synchronous activity per reference spike is preferable to minimize the influence of firing rate. This is particularly relevant for clinical research, in conditions of poorer neuromuscular control.

Changes in cortically induced inhibition in amyotrophic lateral sclerosis with time.

Changes in intracortical inhibition have been detected by means of paired-pulse transcranial magnetic stimulation (TMS) based on electromyographic recordings in many neurological or psychiatric disorders, including amyotrophic lateral sclerosis (ALS). By contrast, inhibitory responses have been generally overlooked in single motor unit (MU) studies in patients with ALS. The aim of this study was to investigate the TMS-induced inhibitory responses of single MUs in peristimulus time histograms and the changes observed with time. For this purpose, 263 MUs were tested in 10 ALS patients in two to four recording sessions. Upon subdividing the data into epochs corresponding to mean disease durations of 12, 20, 32, 43, and 168 months, we found that inhibitory responses occurred more frequently than normal throughout the course of the disease and were stronger than normal during the first year after disease onset. This finding argues against the hypothesis that loss of inhibition may be part of the pathogenic process in ALS.

Approximate entropy of motoneuron firing patterns during a motor preparation task.

The aim of this study was to test whether approximate entropy (ApEn) analysis provides a suitable method of detecting differences induced by a motor preparation task in time-ordered inter-spike intervals (ISIs) recorded in tonically firing motoneurons. Unlike classical methods of analyzing neuronal discharge variability, in which serial order is no taken into account, the approximate entropy (ApEn) was proposed by Pincus [Pincus SM. Approximate entropy as a measure of system complexity. Proc Natl Acad Sci USA 1991;88:2297-301] to analyze ordered series. ApEn statistic is a number assigned to an ordered series, where higher values correspond to greater serial irregularity. In the present study, the activity of 31 single motor units (SMUs) was recorded in human extensor carpi radialis muscles and the ISI durations were analyzed during the performance of a pre-cueing reaction time motor task involving a 3-s preparatory period. ApEn values were computed for each SMU during three steps of the preparatory period and during the preceding control period. Lower ApEn values, were found during preparatory period. The decrease in ApEn values, i.e., the increase in serial regularity, was monotonic from the control to the end of the preparatory period. These results show that ApEn model-independent statistics are a relevant means of detecting changes related to motor preparation in the regularity of time-ordered inter-spike intervals (ISIs).

Enhancement of single motor unit inhibitory responses to transcranial magnetic stimulation in amyotrophic lateral sclerosis.

In healthy human subjects, transcranial magnetic stimulation (TMS) applied to the motor cortex induces concurrent inhibitory and excitatory effects on motoneurone activity. In amyotrophic lateral sclerosis (ALS), a neurodegenerative disease affecting both cortical and spinal motor neurons, paired-pulse studies based on electromyographic (EMG) recording have revealed a decrease in TMS-induced inhibition. This suggested that inhibition loss may promote excito-toxicity in this disease. Against this hypothesis, an abnormally high incidence of inhibitory responses to TMS has been observed in the peristimulus time histograms (PSTHs) in ALS single motor unit studies. The disappearance of cortico-motoneuronal excitatory inputs might, however, have facilitated the detection of single motor unit inhibitory responses in the PSTHs. This question was addressed here using a new approach, where the strength of the excitatory and inhibitory effects of TMS on motoneurone activity was assessed from the duration of inter-spike intervals (ISIs). This analysis was conducted on single motor unit (MU), tested on healthy subjects and patients with ALS or Kennedy's disease (KD), a motor neuron disease which unlike ALS, spares the cortico-spinal pathway. MUs tested on KD patients behaved like those of healthy subjects unlike those tested on ALS patients. The present data reveal that in ALS, the TMS-induced inhibitory effects are truly enhanced during voluntary contractions and not reduced, as observed in paired-pulse TMS studies under resting conditions. The possible contribution of inhibitory loss to the physiopathology of ALS therefore needs to be reconsidered. The present data do not support the idea that inhibition loss may underlie excito-toxicity in ALS.

Progression of cortical and spinal dysfunctions over time in amyotrophic lateral sclerosis.

In view of the conflicting results about the links between lower and upper motor neuron (LMN, UMN) dysfunction in amyotrophic lateral sclerosis (ALS), we undertook this study to correlate their changes over time. Single motor units (MUs) were characterized by their macro-MU potentials, twitch amplitude, and excitatory responses to transcranial magnetic stimulation (TMS). Ten ALS patients were studied 2 to 4 times and their data were subdivided into epochs corresponding to mean disease duration of 12 (58 MUs), 20 (60 MUs), 32 (50 MUs), 43 (40 MUs), and 168 months (55 MUs). The MU size increased and the contractile effectiveness and the excitatory response rates decreased significantly with time. The contractile effectiveness of MUs producing normal excitatory responses decreased with time, whereas a gradual loss of excitatory responses was observed among MUs with normal electromechanical properties. Since no correlation was found between UMN and LMN dysfunction, we conclude that UMN and LMN probably degenerate independently in ALS.

Anticipatory changes in human motoneuron discharge patterns during motor preparation.

The influence of motor preparation on human motoneuron activity was studied by combining single motor unit recording techniques with reaction-time (RT) methods. The tonic activity of wrist extensor motor units associated with voluntary isometric contractions was analysed during preparation for a ballistic wrist extensor muscle contraction, using a time preparation procedure. Two durations of the preparatory period elapsing between the warning signal and the response signal were used in separate blocks of trials: a short preparatory period (1 s) allowing optimum time preparation, and a longer, non-optimum one (3 s). Changes in motoneuron tonic discharge patterns not associated with any changes in the force output were observed during the preparatory period, which suggests that these changes were subtle enough to prevent any changes in muscle contraction from occurring before the forthcoming movement. The changes observed were a lengthening of the mean interspike interval (ISI) and a decrease in the ISI variability. These data confirm that inhibitory mechanisms are activated during motor preparation and suggest that spinal inhibitory mechanisms are involved in the preparatory processes. The mechanisms possibly involved, such as presynaptic inhibition, disfacilitation processes or AHP conductance changes, are discussed. The fact that the preparation-induced effects on motoneuron activity were particularly prominent during the last part of the 3 s preparatory period suggests that they were probably related to the neural processes underlying temporal estimation. The anticipatory changes in motoneuron activity observed here during preparation for action provide evidence that central influences act on spinal motoneurons well before it is time to act.

Cortical versus spinal dysfunction in amyotrophic lateral sclerosis.

Little is known about the possible link between cortical and spinal motor neuron dysfunction in amyotrophic lateral sclerosis (ALS). We correlated the characteristics of the responses to transcranial magnetic stimulation (TMS) with the electromechanical properties and firing pattern of single motor units (MUs) tested in nine ALS patients, three patients with Kennedy's disease, and 15 healthy subjects. In Kennedy's disease, 19 of 22 MUs were markedly enlarged with good electromechanical coupling and discharged with great variability. Their excitatory responses increased with MU size. In ALS, 17 of 34 MUs with excitatory responses behaved as in Kennedy's disease. By contrast, 28 MUs with nonsignificant responses showed poor electromechanical coupling and high firing rates, whereas 28 MUs with inhibitory responses showed moderate functional alterations. This result indicates that in ALS as in Kennedy's disease, sprouting of corticospinal axons may occur on surviving motoneurons. A clear relationship exists between the responsiveness of MUs to TMS and their functional state.

Changes in the inhibitory control exerted by the antagonist Ia afferents on human wrist extensor motor units during an attention-demanding motor task.

The aim of this study was to determine the extent to which an attention-demanding visuomotor task affects the strength of the inhibitory control exerted by the wrist flexor group Ia afferents on the wrist extensor motoneurons. Effects of median nerve stimulation on the tonic activity of wrist extensor single motor units were analyzed in terms of the interspike interval (ISI) lengthening. Results show that the inhibitory effects exerted by the antagonistic group Ia afferents were significantly enhanced when the wrist extensor motoneurons were involved in an attention-demanding task. Enhanced inhibition from antagonist afferents may reflect task-related changes in the excitability of the di- and/or polysynaptic pathways mediating reciprocal inhibition due to either the action of descending inputs and/or an increase in the efficiency of the Ia inputs to the premotoneuronal inhibitory interneurons. Modulation of the inhibition exerted by proprioceptive antagonist afferents may be one of the processes which contribute to the fine adjustment of the wrist muscle force output required in fine handling tasks.

Proprioceptive control of human wrist extensor motor units during an attention-demanding task.

The responsiveness of the tonically firing single motor units (SMU) to Ia afferent volleys elicited by either mechanical (T-reflex) or electrical nerve stimulation (H-reflex) was tested in the extensor carpi radialis muscle (ECR) while the subjects were maintaining a steady wrist extension force using visual feedback set either at low or high gain. The aim was to determine whether the proprioceptive control of tonic motoneuronal activity depends on the level of attentiveness required by the behavioural context. The response probability of the SMUs to tendon taps was significantly higher (p<0.0001) and that to electrical nerve stimulation was lower (p<0.001) during the more demanding task. Since these changes in SMU responsiveness were not accompanied by any differences in either the motor unit firing patterns or the mean levels of EMG muscle activity, it can be concluded that there were no attention-related changes in the net excitatory drive to the ECR motoneurons. These results are consistent with the idea that fusimotor sensitization of the muscle spindle may have occurred in the more demanding task: an increase in the mechanical sensitivity of the muscle spindles would certainly account for both the T-reflex facilitation and the H-reflex depression observed. The attention-demanding task therefore seemed to involve an independent fusimotor drive activation process. The results of this study suggest that an adaptation of the fusimotor system occurs in humans, depending on the levels of attention and accuracy required to perform the ongoing motor task, as previously reported to occur in animals.

Recurrent inhibition of wrist extensor motoneurones: a single unit study on a deafferented patient.

In order to document the effects of recurrent inhibition on the firing times of human alpha-motoneurones during natural motor behaviour, a case study was performed on a deafferented patient. The fact that this subject had completely lost the large-diameter sensory afferents provided us with a unique opportunity of selectively stimulating the motor axons in the nerves. The tonic activity of single motor units (n = 21) was recorded in the extensor carpi radialis muscles while applying randomly timed antidromic electrical stimuli to the radial nerve. The peristimulus time histogram analysis showed the presence of biphasic inhibitory effects, including an early, short-lasting component followed by a longer-lasting component occurring 20-40 ms later. The interspike interval (ISI) during which the stimulation occurred was generally lengthened as compared to the previous ISIs. The stimulation was most effective when delivered early (20-30 ms) after a spike. It was also effective, although less so, when delivered at the end of the ISI (70-100 ms after a spike). The lengthening effect sometimes extended over one or two of the subsequent ISIs. The lengthening effect of the motor axon stimulation was followed by an excitatory-like effect, which took the form of a shortening that affected up to five ISIs after the stimulation. The biphasic inhibitory effects and the subsequent facilitatory effects are discussed in terms of the dual nature of the synaptic processes involved in the recurrent inhibitory network, the postactivation facilitation/depression processes and the mutual inhibition occurring between Renshaw cells.

Pharmacologically induced enhancement of recurrent inhibition in humans: effects on motoneurone discharge patterns.

The aim of the present study was to investigate the effects of spinal recurrent inhibition on human motoneurone discharge patterns. The tonic discharge activity of motor unit pairs was recorded in the extensor carpi radialis (ECR) and abductor digiti minimi (ADM) muscles during voluntary isometric contraction. While undergoing continuous intravenous saline (NaCl 0.9 %) perfusion, the subjects were given a short lasting injection of L-acetylcarnitine (L-Ac), which has been found to potentiate recurrent inhibition in humans. The variability, synchronization and coherence of the motor unit discharges were analysed during four successive test periods (lasting 2-3 min each). A significant decrease in the inter-spike interval (ISI) coefficient of variation was observed in the discharge patterns of the motor units tested in the ECR and not in the ADM, which were not accompanied by any consistent changes in the mean ISIs of the motor unit activity in either muscle. The L-Ac injection also led to a significant increase in the synchronization in half of the motor unit pairs tested in the ECR muscle (n = 29), whereas no consistent changes were observed with the ADM motor units (n = 25). However, coherence analysis failed to reveal any consistent differences in the incidence of significant values of coherence spectrum between the pre-injection and injection periods among the motor unit pairs tested with either saline or L-Ac injections, in either the ECR or ADM muscles. The contrasting effects on the variability and the synchronization of the motor unit discharges observed with ECR motoneurones known to undergo recurrent inhibition and with ADM motoneurones known to lack recurrent inhibition suggest that the drug may have specific effects which are mediated by an enhancement of the Renshaw cell activity. The decrease in the ISI variability is in line with the hypothesis that recurrent inhibition may contribute along with the post-spike after-hyperpolarization to limiting the influence of the synaptic noise on the firing times of steadily discharging motoneurones. The present data, which suggest that recurrent inhibition plays a synchronizing rather than a desynchronizing role, are in keeping with the fact that the Renshaw cells may provide an important source of common inhibitory inputs.

Presynaptic and disynaptic inhibition induced by group I muscle afferents.

The task related changes in the Gp I inputs were investigated in type-identified motor units in the wrist extensor muscles. During wrist extension, the monosynaptic inputs generated by applying radial nerve stimulation were distributed among the motoneurone pool in line with the size principle. Their effectiveness was enhanced in the same way during hand clenching and during wrist extension combined with stimulation of the palm and finger cutaneous receptors. The orderly distribution of the monosynaptic Gp I inputs was reversed by the presynaptic inhibition induced by stimulating the Gp I flexor afferents. The effects of the presynaptic inhibition were partially released by applying cutaneous stimulation. During wrist extension, the Gp I flexor afferents generated disynaptic excitatory inputs acting specifically on high-threshold motor units together with disynaptic inhibitory inputs distributed in line with the size principle among the wrist extensor motor nucleus. During hand lenching, their effectiveness was differentially modulated depending on the motor unit type.

Delayed and prolonged effects of a near threshold EPSP on the firing time of human alpha-motoneurones.

In order to investigate the effects of near-threshold excitatory inputs on the precise timing of the action potentials during the tonic discharge of human motoneurones, the activity of single motor units was recorded in the extensor carpi radialis muscles while tendon taps (indentation, 0.1 mm; duration, 1 ms) were being delivered irregularly at a mean rate of 0.8 s(-1). New methods of analysis, such as the phase response function, were used to study the relative changes in the interspike interval (ISI1) during which the stimulus was being delivered and in the three subsequent intervals (ISI2, ISI3, ISI4) as a percentage of the pre-stimulus interspike interval (ISI0). The consistency of the effects of the actual stimulus as regards the spontaneous variability was assessed by comparing the data with those obtained with virtual stimulation. When the stimulus occurred at the end of ISI1, and triggered a spike, ISI1 and ISI3 were generally shortened, whereas ISI2 was lengthened, probably due to the negative correlation induced by the summation of the after-hyperpolarisations (AHPs). When the stimulus occurred in the middle of ISI1 without triggering a spike, ISI1, ISI2 and more rarely ISI3 were shortened. Lastly, when the stimulus occurred during the AHP scoop in ISI1, ISI2 was shortened although ISI1 remained unchanged. ISI4 was not consistently affected in any of these cases. The present results show that the tendon tap-induced inputs (probably from muscle spindle primary endings) mediated delayed and prolonged shortening effects of the ISIs on most of the alpha-motoneurones tested (n = 16). These effects undetected in classic peri-stimulus histogram analysis may involve long-lasting conductance changes although the contribution of polysynaptic pathways cannot be excluded. The changes in ISI were quite moderate (< 15% of ISI) but highly consistent. Their functional involvement in the synchronisation or desynchronisation processes and/or the mechanisms of optimisation of muscle contraction still remains to be explored.