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. 2017 Jun 14;118(2):1355–1360. doi: 10.1152/jn.00233.2017

Excitability and firing behavior of single slow motor axons transmitting natural repetitive firing of human motoneurons

Lydia P Kudina 1,✉, Regina E Andreeva 1
PMCID: PMC5558025  PMID: 28615333

Excitability of single slow axons was estimated by motor unit firing index in response to motor nerve stimulation, and its changes throughout a target interspike interval were explored during transmitting human motoneuron natural firing. It was found that axons exhibited early irresponsive, responsive, and later irresponsive periods. Findings question whether the traditionally described axonal excitability recovery cycle is realistic in natural motor control.

Keywords: motor control, human motoneuron natural firing, single slow motor axons, axonal excitability, axonal firing behavior

Abstract

Excitability of motor axons is critically important for realizing their main function, i.e., transmitting motoneuron firing to muscle fibers. The present study was designed to explore excitability recovery and firing behavior in single slow axons transmitting human motoneuron firing during voluntary muscle contractions. The abductor digiti minimi, flexor carpi ulnaris, and tibialis anterior were investigated during threshold stimulation of corresponding motor nerves. Motor unit (MU) firing index in response to testing volleys evoking M-responses was used as a physiological measure of axonal excitability and its changes throughout a target interspike interval (ISI) were explored. It was shown that axons displayed an early irresponsive period (within the first ~2–5 ms of a target ISI) that was followed by a responsive period (for the next 5–17 ms of the ISI), in which MUs fired axonal doublets, and a later irresponsive period. At the beginning of the responsive period, M-responses showed small latency delays. However, since at that ISI moment, MUs displayed excitability recovery with high firing index, slight latency changes may be considered as a functionally insignificant phenomenon. The duration of axonal doublet ISIs did not depend on motoneuron firing frequencies (range 4.3–14.6 imp/s). The question of whether or not traditionally described axonal recovery excitability cycle is realistic in natural motor control is discussed. In conclusion, the present approach, exploring, for the first time, excitability recovery in single slow axons during motoneuron natural activation, can provide further insight into axonal firing behavior in normal states and diseases.

NEW & NOTEWORTHY Excitability of single slow axons was estimated by motor unit firing index in response to motor nerve stimulation, and its changes throughout a target interspike interval were explored during transmitting human motoneuron natural firing. It was found that axons exhibited early irresponsive, responsive, and later irresponsive periods. Findings question whether the traditionally described axonal excitability recovery cycle is realistic in natural motor control.

in normal motor behavior, the main function of motor axons is the propagation of alpha motoneuron repetitive firing to muscle fibers that they innervate. Excitability of motor axons is a fundamental property governing that function. The excitability recovery cycle in single motor axons after spike transmission has been thoroughly examined in animal preparations. The current belief is that each spike is followed by stereotyped changes in axonal excitability, called the absolute and relative refractory periods, the supernormal and late subnormal periods. As healthy motor axons transmit motoneuron repetitive firing to muscle fibers in the “one-to-one” fashion, motoneuron firing can be explored in humans, analyzing single motor unit (MU) recordings (see Burke 1981; Heckman et al. 2009; Kernell 2006). Such an approach allows exploring single human axon properties as well. Nevertheless, as noted by Trevillion et al. (2010), presumably because of the difficulty of isolating and tracking single motor axons, the human axon excitability recovery cycle was traditionally explored, using compound muscle action potential (CMAP) evoked by nerve trunk stimulation (see for review Burke et al. 2001). As a result, the human motor axon excitability recovery cycle was commonly studied for whole alpha motoneuron pools. However, as emphasized by Heckman and Enoka (2012), in contrast to the ease of recording CMAP, “its interpretation is more challenging.” Matthews (1999) noted that the interpretation of summed electromyogram implicitly depends upon the accumulated knowledge of single MU properties. Therefore, it is important to explore the excitability recovery in single human motor axons belonging to single MUs with different excitability properties, in particular, small, slow MUs (higher threshold to electrical axonal stimulation) and larger, faster MUs (low threshold to axonal stimulation).

However, only in a few reports, beginning with seminal studies of Bergmans (1970, 1973), single motor axon excitability has been examined (e.g., Borg 1983; Bostock et al. 2005; Hales et al. 2004; Shefner et al. 1996; Trevillion et al. 2010). As a rule, in these reports, fast, low-threshold to electrical stimulation axons during supramaximal conditioning and submaximal testing stimuli were studied. At the same time, single slow motor axons belonging to small MUs being commonly higher-threshold to electrical stimulation are not usually explored. However, it deserves emphasis that namely these MUs present an important part of alpha motoneuron pool as namely they are primarily recruited in normal motor behavior during reflex activations, gentle and moderate voluntary contractions, and postural tasks. Their investigation is important as well for understanding underlying mechanisms of many neuromuscular disorders. Padua (2012), in a list of the issues that are difficult to investigate but that must be explored, has included the investigation of single slowly-conducting axons as they “are likely responsible for most of the diseases and dysfunctions that we are not able to assess.”

The aim of the present study was to explore excitability and firing behavior of single slow motor axons during transmitting motoneuron natural repetitive firing evoked by voluntary muscle contractions in healthy humans.

METHODS

Fifteen experiments were performed in six healthy volunteers (aged 33–62 yr). Each subject gave informed, written consent to participate in the experiments, which were approved by the local Ethics Committee and conformed to the Declaration of Helsinki. The present data were obtained in part from experiments already reported during the study of other issues, in particular, some characteristics of MU firing originated in motoneurons and axons (Kudina and Andreeva 2014, 2016) but mostly from new experiments.

Experimental protocol.

The subjects were comfortably seated in an armchair. They were asked to recruit a few MUs by gentle voluntary isometric contraction of one of three muscles investigated and to maintain MU steady firing, using visual and audio feedback of MU action potentials, which were recorded by means of a bipolar needle electrode (leading-off surfaces of 0.015 mm2), amplified by an electromyograph DISA at 200–500 μV/cm, with filters set at 20 Hz to 10 kHz and stored on the magnetic tape for off-line analysis. The following muscles were investigated: a muscle of the hand, the abductor digiti minimi (ADM); a muscle of the forearm, the flexor carpi ulnaris (FCU); and a muscle of the leg, the tibialis anterior (TA).

While the subject maintained voluntary contraction for 60–130 min (continuous or interrupted by 1- to 2-min relaxations), single threshold stimuli (13–23 V), random in relation to MU firing, were applied through a bipolar surface electrode to the ulnar nerve (at the wrist or at the elbow during ADM or FCU studies, respectively), or to the common peroneal nerve (at the head of the fibula during TA studies). The duration of single stimuli commonly was of 1 ms (in some experiments the interstimulus interval of 1-s duration was used). In different experiments, the number of stimuli applied to motor nerves (i.e., number of testing axonal volleys) ranged from 738 to 2,249. The tolerance of the subject to the electrical nerve stimulation in each given experiment was the main criterion of the choice of the interstimulus interval and number of testing volleys with the aim to avoid any discomfort for our subjects.

During gentle voluntary contractions, low-threshold MUs with thin axons are preferentially recruited. These axons tend to be higher-threshold to electrical stimulation, and their activation during low-intensity stimulation is rather a challenge. Thereby the stimulus intensity and particularly a position of the stimulating electrode were adjusted manually until an axon of a single firing MU was stimulated and its M-responses evoked by testing axonal volley were clearly identifiable. Such an approach of manual adjusting a position of the stimulating electrode and the stimulus intensity for exploring single human axons was previous applied by Bergmans (1970, 1973), Hales et al. (2004), and Bostock et al. (2005).

Data analysis.

The MU action potentials were transferred to a computer by an A/D converter (Russia, type L-Card 154), with a sampling rate of 10 kHz. Each MU was identified based on the shape and amplitude of its action potentials. The results of the preliminary computer MU identification were then verified by the experienced operator. Great care was taken to confirm the MU identification throughout the experiment. Only the sections of records with 100% proper identification were accepted for further analysis.

The firing index (FI) was used as an indirect quantitative measure of axonal excitability (Kudina and Andreeva 2014). At multiple testing, for each MU, all trials were subdivided into groups in relation to the arrival moment (timing) of the testing axonal volley within a given ISI (a target ISI) with a step of 1 or 2 ms, depending on the number of stimuli delivered in a given experiment. The FI, showing the percentage of evoked MU discharges at the M-response latency to the total number of the testing volleys arriving in a given moment of a target ISI, was calculated and FI changes throughout a target ISI were analyzed. This gave the possibility to estimate axonal excitability recovery after propagation of a natural motoneuron discharge during voluntary muscle contraction.

Next, the latencies of single MU M-responses were estimated and analyzed in relation to timing of the testing volley within a target ISI.

The mean discharge rates of MU background firing were calculated for 0.5 s before a stimulus. For each MU, in each trial, the ISI between a last regular motoneuron discharge and an evoked M-response (the axonal ISI) were estimated. Group data are presented in the text as the mean values and their SDs. The relation between axonal ISIs of single MUs and their mean background firing frequency was analyzed. For this, the data for a given MU obtained from many trials were pooled and the regression lines referring to the data of each plot were fitted. For statistical estimation, Pearson correlation coefficients were calculated between the pooled values. All differences were considered as statistically significant at P < 0.05.

RESULTS

Firing behavior of 93 MUs (including 36 MUs of ADM, 25 MUs of FCU, and 32 MUs of TA) was analyzed. In muscles investigated, during gentle voluntary contractions, MU mean firing rates were rather close and commonly tend to lie between 4 and 15 imp/s. In response to motor nerve stimulation, 44/93 firing MUs (45.9%) exhibited evoked discharges (n = 628) at M-response latency, including 21 MUs of ADM (88 M-responses), 8 MUs of FCU (115 M-responses), and 15 MUs of TA (425 M-responses). MUs (20/44; 45.5%) that produced 586 M-responses were analyzed in detail. Figure 1 provides representative instances of MU recordings. The remaining 24 MUs, which have shown 42 M-responses only (from 1 to 4 per an MU), were excluded from the further analysis.

Fig. 1.

Fig. 1.

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Firing behavior of single MUs activated by gentle voluntary muscle contractions. TA, tibialis anterior, ADM, abductor digiti minimi; FCU, flexor carpi ulnaris. Points: regular discharges of MUs tested; asterisks: stimulation time of corresponding motor nerve; M: the M-responses. Time bar: 5 ms (for the insets) and 50 ms (for the other recordings).

Testing excitability recovery in single slow motor axons after transmitting a regular motoneuron discharge.

The possibility of M-response occurrence critically depended on timing of a testing volley within a target ISI, i.e., on axonal excitability recovery following the propagation of a regular motoneuron discharge (Figs. 2 and 3A). In all MUs investigated, when testing volleys arrived at the beginning of a target ISI (within the first 2.1–4.7 ms), axons failed to respond to the testing volley and FI was equal to 0% (the early irresponsive period). Further, the responsive period began; the same testing volley became effective and MUs could fire M-responses. FI increased, quickly reaching maximal values (up to 85–100%) at 4–12 ms of a target ISI. Thereafter, in most of the MUs tested (16/20), in some trials, axons did fire in response to motor volley while in the other trials they did not; respectively, FI gradually decreased. In 10–20 ms after a regular discharge, stimuli became completely ineffective and FI appeared equal to 0% (the later irresponsive period, up to the following regular MU discharge evoked by voluntary muscle contraction). Four MUs of FCU did not have the later irresponsive period. Thus excitability recovery testing in most of the slow axons transmitting natural motoneuron firing has revealed three phases: the early irresponsive period, responsive period, and later irresponsive period.

Fig. 2.

Fig. 2.

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Example of single MU recordings during excitability recovery testing of its axon transmitting motoneuron repetitive firing during gentle voluntary muscle contraction. TA, tibialis anterior. Timing of testing motor volley within a target ISI, from top to bottom: 2.4 ms (the MU did not fire the M-response); 4.8 and 6.3 ms (the MU fired the M-response at delayed latency of 10.3 ms and at usual latency of 9.6 ms, respectively); 14.2 ms (the MU did not fire the M-response again). Points: the last regular voluntary discharge of the MU tested; asterisks: the stimulation time of motor nerve; M: the M-responses. Time bar: 5 ms.

Fig. 3.

Fig. 3.

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Excitability recovery testing of a single slow axon transmitting motoneuron repetitive firing during gentle voluntary muscle contraction. TA, the tibialis anterior. A: abscissa, timing of the motor volley within a target ISI. The moment of the last regular voluntary discharge is taken as 0 ms (the bin width: 2 ms). Ordinate, FI (a number of the M-responses calculated for each bin as the percentage of a common number of testing motor volley arriving in a given bin). A total of 1,620 trials were performed; M-responses were recorded in 144 trials. FI changes are shown within the first 30 ms of the target ISI (in the remaining part of the ISI, FI continued to be equal to 0% up to the following regular voluntary MU discharge). Note the highest FI values within the bins of 4–8 ms. B: abscissa, the same as in A. Ordinate, M-response latency. Note the delayed latency at timing of 4–7 ms.

Latency and amplitude of M-response during responsive period of axonal excitability recovery.

When the motor volley arrived at the beginning of the responsive period, M-responses displayed delayed latency (Figs. 2 and 3B). These delays in latency were small but were invariably found in most MUs. It deserves emphasis that the evoked axonal discharges with the delayed latency were paralleled by the high FI value, i.e., the axonal excitability was recovered (cf., Fig. 3, A and B).

Note also that in most MUs tested, amplitude of M-responses was frequently smaller than that of regular voluntary discharges of a given MU. Changes in the amplitude commonly appeared to be more prolonged than those in M-response latency. Such effects were consistently observed. It should be emphasized that this factor can bring the possibility of the misleading interpretation of the estimation of the axonal excitability recovery cycle, traditionally using CMAP amplitude. In addition, it should be kept in mind that such a property of the interference electromyogram, which was termed “amplitude cancellation” (e.g., Farina et al. 2008; Keenan et al. 2005), must critically trouble this estimation.

ISIs of axonal doublets and their relation to background motoneuron firing frequency.

The MU response to an axonal testing volley commonly resulted in the occurrence of peculiar firing that may be called “axonal doublets” in which the first potential was a regular motoneuron discharge while the second one was evoked by axonal electrical stimulation eliciting the M-response. For 19/20 MUs, ISIs of axonal doublets were in the range of 3.4–20.0 ms (10.2 ± 3.8) and only one MU from TA demonstrated an axonal doublet with shorter ISI (2.2 ms).

In several MUs (2 MUs of TA, 1 of FCU and 1 of ADM), very unusual doublets were recorded (n = 8), in which both discharges had the axonal origin: the first one was the M-response and the second occurred in 2.7–14.0 ms (mean 7.5 ms), i.e., in these cases, the axons, themselves, occasionally fired a natural discharge (without stimulation) in a few milliseconds after a prior evoked discharge, creating a specific axonal doublet. Note that ISIs of these doublets were in the same range as those of axonal doublets above in which the second discharge was elicited by motor nerve stimulation. This provided some evidence that given experimental conditions can be used to mimic the effects of natural axonal activation.

We next analyzed whether an axonal doublet ISI changed at different background MU discharge rate that is a main characteristic of a firing motoneuron. Eleven MUs, which showed the wider range of background firing rates, were explored (6 MUs in TA, 3 MUs in FCU and 2 MUs in ADM). The mean background firing rates ranged from 4.3 to14.6 imp/s (mean ISIs from 68.5 to 232.6 ms). ISIs of axonal doublets (n = 509) were in the range of 3.4–20.0 ms (10.0 ± 3.8 ms). It was found that in all MUs analyzed, axonal doublet ISIs did not vary significantly with motoneuron firing rate. Correlation coefficients ranged from 0.026 to 0.387 (P > 0.05). Representative instances are shown in Fig. 4. Thus, in a physiological range of motoneuron firing rates, during gentle voluntary muscle contraction, ISIs of axonal doublets did not depend on motoneuron firing rate.

Fig. 4.

Fig. 4.

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The relation between mean background firing frequencies of single motoneurons activated during gentle voluntary muscle contractions and interspike intervals of axonal doublets evoked by motor nerve stimulation. A, B, C: three single MUs are presented. TA, the tibialis anterior; ADM, the abductor digiti minimi; FCU, the flexor carpi ulnaris. Regression lines are superimposed on the data (n = 152, n = 47, and n = 75, respectively). The correlation coefficients are not significant (r = 0.038, r = 0.017, and r = 0.026, respectively; P > 0.05).

DISCUSSION

The present study provides the data on excitability and firing behavior of single slow motor axons transmitting alpha motoneuron natural repetitive firing during voluntary muscle contractions in healthy humans. To our knowledge, the issue has not been investigated before.

Our approach differed from that in traditional study of human axon excitability recovery in a number of aspects, the most essential being that we based it on the assumption that the most functionally significant criterion of excitability recovery in an axon is the occurrence of axonal spike by itself. Consequently, the presence or absence of the evoked discharge at the M-response latency of a given MU (estimated by FI) gave unequivocal evidence of whether or not excitability in the axon was recovered. Thus the change in FI throughout a target ISI was used as an indirect quantitative measure of axonal excitability recovery after transmitting a natural discharge of a physiologically activated alpha motoneuron. Our data showed that for most MUs displaying M-response, three periods could be revealed during axonal excitability recovery after propagation of a motoneuron discharge: early irresponsive, responsive, and later irresponsive periods.

Traditionally, for exploring this question, an estimation of changes in stimulus strength required to produce a test, submaximal CMAP of the given amplitude (commonly 30–50% max) following a supra-maximal conditioning stimulus was used and stereotyped changes in axonal excitability were revealed: the absolute and relative refractory periods, the period of supernormality (or superexcitability) and the late subnormal (or subexcitable) period (see for review Burke et al. 2001; Nodera and Kaji 2006). It should be pointed out that in these conditions the testing stimulus activated only fast motor axons (having low thresholds to electrical stimulation), which, as was noted by Trevillion et al. (2010), may not be representative of the whole alpha motoneuron pool, at least for some properties. Moreover, one may assume that estimation of the axonal state by the change in stimulus strength provides little physiological insight into single axon firing behavior during natural motor control when a given motoneuron produces always one and the same message, a spike, which its axon transmits to muscle fibers in the “all-or-none” fashion. In this case, following Bergmans (1970), “it may be asked if the different phases of the recovery cycle described have a meaning in the normal functioning of the nervous system.” In response to the question, it is difficult to avoid the suggestion that the axonal excitability recovery cycle revealed by increasing and decreasing in stimulus strength probably is a physiological abstraction absent in normal motor behavior. Therefore, in the limits of our approach, neutral terms such as the “irresponsive period” [first coined by Lucas (1909)], when an axon did not fire a spike in response to a testing volley, and the “responsive period,” when an axon fired a spike, are presumably more preferable as they are more corresponding to real firing behavior of axons.

During the traditional approach using CMAP, commonly addressed to fast axons, excitability during the relative refractory and supernormal periods was usually sampled at conditioning-test intervals of 2 and 7 ms, respectively (e.g., Kuwabara et al. 2001), i.e., it was supposed that the absolute refractory period had duration <2 ms. All axons in the present study were of slow ones; consequently, no direct comment can be made about the fast axons. However, note that the duration of the early irresponsive period estimated in the present study for slow axons was longer (range of ~2–5 ms) than that of the absolute refractory period reported for fast axons. At the same time, the total duration of the early irresponsive and responsive periods in our experiments for most MUs was similar to that of the refractory period (absolute and relative) and the supernormal period observed for fast axons, commonly being in limits of ~20 ms.

A critical complication in axonal excitability estimations when using both CMAP and single MU recordings is the M-response delayed latency observed at short conditioning-test intervals. Traditionally, delayed latency was considered as a sign of the relative refractory period and returning to usual latency served to indicate its end (e.g., Borg 1983; Gilliatt and Willison 1963). Moreover, in some studies (e.g., Borg 1983) it was concluded that the delayed latency limited the MU discharge frequency. According to our data, at the beginning of the responsive period, when slow MUs responded with the delayed latency, their responses were characterized by high (up to maximal) FI, i.e., axonal excitability was recovery. It should be emphasized as well that the changes in latencies were very slight and, therefore, we believe, could hardly be functionally significant for the information transmission from a motoneuron to muscle fibers, since no spike is added or lost because of them. Besides, the delaying was characteristic only for doublet firing with minimal ISIs (typically in the range of ~3–6 ms), which is not a fundamental pattern of MU firing behavior during normal movements. It must be pointed out as well that this lengthening was essentially smaller than common ISI scatter during natural motoneuron firing, including doublets. Thus we suggest that slight latency delaying is not functionally important.

In normal motor behavior, an axon has the only main function, to transmit motoneuron firing to muscle fibers, and therefore presumably it must be the one entity with its motoneuron. Consequently, the axonal excitability recovery cycle has to be some counterpart of that in the motoneuron, which includes first such an important motoneuronal property as a prolonged post-spike afterhyperpolarization inevitably following each spike in each motoneuron. And only some of motoneurons have a short period of superexcitability, related to the delayed depolarization (the depolarizing afterpotential) preceding the onset of the afterhyperpolarization (Calvin and Schwindt 1972; Granit et al. 1963; Kernell 1964, 2006). As a result, in only some motoneurons, occasional doublets were recorded in both acute animal experiments (e.g., Calvin 1974; Calvin and Schwindt 1972; Hoff and Grant 1944; Kernell 2006) and in human gentle voluntary muscle contractions (e.g., Bawa and Calancie 1983; Denslow 1948; Garland and Griffin 1999; Kudina 1974; Kudina and Andreeva 2010, 2013).

In contrast, all axons, as it may be concluded from the analysis of whole alpha motoneuron pool, using CMAP (Burke et al. 2001; Nodera and Kaji 2006), demonstrate the superexcitability period in the recovery cycle. As for single axons, the superexcitability period in human single motor axons is apparently their constant feature (Bergmans 1970; Gilliatt and Willison 1963) that can potentially result in axonal doublets. An obvious question is what are the functional benefits of such an axonal property? This important question remains presently unanswered in normal motor behavior and requires further investigation. However, in diseases, it may be assumed that axons possessed by marked superexcitability can be more predisposed to dysfunctions, in particular, to spontaneous firing. As noted by Burke (2007), many diseases primarily affect the axon rather than the motoneuron.

GRANTS

This work was supported by Russian Science Foundation Grant 14-50-00150.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

L.P.K. conceived and designed research; L.P.K. and R.E.A. performed experiments; L.P.K. and R.E.A. analyzed data; L.P.K. and R.E.A. interpreted results of experiments; L.P.K. drafted manuscript; L.P.K. and R.E.A. edited and revised manuscript; L.P.K. and R.E.A. approved final version of manuscript.

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