Evaluation of plateau-potential-mediated ‘warm up’ in human motor units
1 Department of Physiology, College of Medicine, University of Arizona, Tucson, AZ, USA
Abstract
Spinal motor neurones can exhibit sustained depolarization in the absence of maintained synaptic or injected current. This phenomenon, referred to as a plateau potential, is due to the activation of monoamine-dependent persistent inward currents. Accordingly, activation of a plateau potential should result in a decrease in the excitatory synaptic drive required to activate a motor unit. This, in turn, has been suggested to cause a progressive decline in the muscle force at which motor units are recruited during repeated voluntary contractions. Such a progressive decrease in threshold force associated with preceding activation of a plateau potential is referred to as ‘warm up’. Furthermore, activation of a plateau potential is thought to manifest itself as a decrease in the derecruitment force compared to recruitment force. Multiple muscles, however, can contribute to the detected force and their relative contributions may vary over time, which could confound measures of recruitment and derecruitment force. Therefore, the purpose of this study was to compare the recruitment and derecruitment forces of single motor units in the human extensor digitorum and tibialis anterior during repetitive triangular-force contractions in which the contributions of other muscles had been minimized. In both muscles, we found that the recruitment thresholds of single motor units were unchanged during repeated contractions, and that the derecruitment force was consistently greater than the recruitment force. These results suggest either that plateau potentials were not engaged (or were rapidly extinguished) under these experimental conditions or that changes in recruitment and derecruitment force are not suitable criteria for detecting them.
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Introduction
A plateau potential is a sustained depolarization that can be maintained for several seconds after synaptic excitation (or intracellular current injection) has been reduced or removed (Hounsgaard et al. 1984, 1988). In vertebrate motor neurones, the sustained depolarization appears to be caused by the activation of voltage-gated, slowly inactivating inward currents (referred to as persistent inward currents), primarily those mediated by Ca2+ entering through L-type channels (Hounsgaard & Kiehn, 1985, 1989;. Hounsgaard & Mintz, 1988; Perrier & Hounsgaard, 2003). In order for these channels to be activated by depolarization (10–30 mV from the resting potential, Alaburda et al. 2002), they first must be enabled by an intracellular biochemical cascade that is instigated by the binding of various neuromodulators (Rekling et al. 2000), such as monoamines to dendritic metabotropic receptors (Perrier et al. 2000; Perrier & Hounsgaard, 2003). Axons projecting from nuclei in the brain stem provide the primary source of monoamines (e.g. as serotonin and noradrenaline) to spinal neurones through direct synaptic contacts (Alvarez et al. 1998; Maxwell et al. 2000). Indeed, electrical stimulation of the raphe nucleus in isolated brain-stem–spinal-cord preparations has been shown to promote plateau potentials in turtle spinal motor neurones (Perrier and Delgado-Lezama, 2005). Furthermore, monoamine-dependent persistent inward currents and associated plateau potentials have been demonstrated in spinal motor neurones of reduced preparations in a variety of other vertebrate species (see reviews by Kiehn, 1991; Hultborn & Kiehn, 1992; Hornby et al. 2002; Heckman et al. 2003, 2005).
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The possible functional roles of plateau potentials, however, remain a matter of debate (Hornby et al. 2001). To resolve this issue, it is necessary to determine whether, and under what conditions, plateau potentials are activated in intact animals. An unequivocal demonstration of plateau-potential expression requires that the magnitude of synaptic input be known. This factor represents a largely insurmountable obstacle in attempts to identify plateau potentials in intact animals. Nevertheless, a number of criteria have been proposed as evidence for activation of plateau potentials based on the discharge behaviour of motor units recorded in intact humans during voluntary contractions (Kiehn & Eken, 1997; Heckman & Lee, 1999; Gorassini et al. 2002a,b; Hornby et al. 2002). In particular, it has been suggested that activation of a plateau potential during a contraction should diminish the excitatory synaptic drive needed subsequently to recruit (or de-recruit) motor neurones. Such lowering in threshold is thought to manifest itself in motor unit recordings as a decrease in derecruitment force compared to recruitment force, and as a progressive decline in recruitment force during repeated contractions (Gorassini et al. 1998; Bennett et al. 1998; Heckman & Lee, 1999; Hornby et al. 2002). Other evidence for threshold-lowering associated with activation of plateau potentials has been inferred based on the relative change in firing rates of control units (rather than on muscle force) at the times of recruitment and derecruitment of simultaneously recorded test units (Kiehn & Eken, 1997; Gorassini et al. 1998, 2002a,b; Bennett et al. 2001; see Discussion). The reduction in threshold (measured in terms of force or control-unit firing rate) associated with the preceding activation of a plateau potential is referred to as ‘warm up’ (Bennett et al. 1998).
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An alternative explanation for ‘warm up’, as evidenced by a reduction in threshold force, is that during triangular ramp contractions involving precise increases and decreases in force, antagonist muscles may be slightly more active during the decreasing force phase (De Luca & Mambrito, 1987). Such antagonist muscle activity would reduce the net torque at the joint and thereby lower the measured force. Therefore, activity in antagonist muscles can give rise to the appearance of decreased derecruitment thresholds (Patten & Kamen, 2000). Furthermore, such antagonist activity might carry over into an immediately following ramp contraction and cause an apparent drop in recruitment threshold.
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The purpose of the present study therefore was to compare recruitment and derecruitment thresholds of single motor units in extensor digitorum (ED), a muscle involved in controlling the fingers, and tibialis anterior (TA), a postural muscle, during repetitive contractions in which the contributions of antagonistic muscles had been minimized. This was accomplished by positioning the joints of the hand and ankle in such a way so as to hold antagonistic muscles at short lengths and thereby undermine their ability to generate force. Consequently, ‘warm-up’-related changes in thresholds of recruitment or derecruitment, if observed, could be more confidently attributed to plateau-potential mediated effects rather than as a result of activation of antagonist muscles.
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Methods
A total of 27 experiments were performed in 18 healthy human volunteers (nine women, nine men, ages 21–43 years). The experimental procedures were approved by the Human Investigation Committee at the University of Arizona. All subjects gave their informed consent to participate in the study. Fifteen experiments were performed on the compartment of ED that controls digit 3 of the right hand, and 12 experiments were carried out on the TA of the right leg. The ED was selected for study because it has virtually no synergists for extension of the metacarpalphalangeal (MCP) joint of digit 3. The TA was selected because motor units in this muscle have been shown previously to exhibit responses considered to be indicative of plateau potentials (Kiehn & Eken, 1997; Gorassini et al. 1998, 2002a,b; Collins et al. 2002).
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Experimental set-up
Details of the experimental arrangement for experiments involving the digit 3 compartment of ED have been provided previously (Keen & Fuglevand, 2003). Briefly, subjects were seated comfortably in a dental chair with their right elbow and wrist supported and immobilized. The elbow was flexed at approximately 30 deg from full extension, the wrist was flexed about 45 deg, and the hand was orientated midway between fully supinated and fully pronated with the thumb pointing upwards. The MCP joints were maintained in a fully flexed position (90 deg of flexion) by metal cuffs around the proximal interphalangeal joints that were attached to separate force transducers via light-weight cables. With this hand position, the finger flexors were held at shortened lengths, which minimized their ability to generate force. In a separate series of experiments carried out in five subjects, the mean (±S.D.) maximum voluntary contraction (MVC) force for digit 3 flexion in this shortened configuration was 38 ± 21% of that generated when the MCP joint was held in a neutral (180 deg) position.
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For experiments that examined motor units in TA, subjects were comfortably seated in a dental chair with their knee flexed by about 30 deg. The foot was secured to a cantilevered metal foot plate with a Velcro strap and the heel of the fool rested in a thermoplastic cup. A strain-gauge transducer was attached to the foot plate to measure dorsiflexion force. The foot plate was mounted on an adjustable platform that was tilted individually for each subject in order to hold the ankle joint in full plantar flexion. This greatly reduced the capacity of the plantar flexor muscles to exert force. In separate set of experiments carried out in four subjects, the MVC force associated with plantar flexion in this position was 18 ± 10% of that exerted when the ankle was held in a neutral orientation (i.e. 90 deg angle between plantar surface of foot and longitudinal axis of tibia).
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Force and EMG recording
Extension forces of the digits were measured by four force transducers (range of 0–5 N and sensitivity of 780 mN mV–1; Grass Instruments, Warwick, Rhode Island, USA); however, only the force recordings from digit 3 were analysed. The force transducers were mounted in a custom-built manipulandum that allowed each transducer to be aligned with the proximal interphalangeal joint of the appropriate finger. A less sensitive force transducer (range of 0–400 N and sensitivity of 56 N mV–1) was used to measure foot dorsiflexion force for the TA experiments. The force signals from ED or TA were amplified (x1000) and displayed on an oscilloscope and a computer monitor.
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Motor unit action potentials were recorded with sterilized tungsten microelectrodes inserted into the digit 3 compartment of ED or into TA (Frederick Haer and Co. Bowdoinham, Maine, USA; 1–5 μm tip diameter, 5–10 μm uninsulated length, 250 μm shaft diameter, 200 k impedance at 1000 Hz after insertion). Weak electrical stimulation was used initially to verify microelectrode placement in the digit 3 compartment of ED based on the magnitude of the force evoked by the stimulation on digit 3 compared with the other fingers (Keen & Fuglevand, 2003). A surface electrode (4 mm diameter, Ag–AgCl) attached to the skin overlying the radius served as the anode during stimulation. The same electrode served as the reference electrode during motor unit recording in ED. For TA experiments, a surface electrode placed over the tibia served as the reference electrode. The intramuscular electromyographic (EMG) signals were differentially amplified (x1000), band pass filtered (0.3–3 kHz) (Grass Instruments), displayed on an oscilloscope, and routed to an audio amplifier. Force and EMG signals were digitized at a rate of approximately 2 and 20 kHz, respectively (Cambridge Electronic Design Ltd, Cambridge, UK).
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Protocol
Initially, subjects performed weak isometric contractions of ED or TA by attempting to extend digit 3 or dorsiflex the foot, respectively. During these contractions, the microelectrode was manipulated until the action potentials of a motor unit could be clearly identified. Once the discharge potentials of at least one motor unit could be identified from the intramuscular EMG signals, subjects performed two consecutive triangular isometric force ramps (referred to as phase 1 and phase 2 of the trial) (Fig. 1). Using visual feedback of force on a computer display, subjects attempted to steadily increase and then decrease finger extension or foot dorsiflexion force and to generate the same force profile for both phases. Subjects were instructed to keep the limb relaxed prior to the onset of the contraction, and then to increase the force during the ramp beyond that needed to recruit the unit under study, but to not exceed force levels that might lead to excessive activation of several other units. Therefore, the absolute force exerted during the triangular force ramps varied from one unit to another. After the two phases, subjects rested for approximately 30 s before performing another trial of two successive triangular force ramps. This duration (30 s) of rest period was chosen because plateau potentials are thought to dissipate within 5–6 s following a contraction (Svirskis & Hounsgaard, 1997; Bennett et al. 1998; Gorassini et al. 2002b). Consequently, it was assumed that following 30 s of rest and immediately prior to the outset of each trial, plateau potentials were not present in motor neurones. Each unit was tested during between three and five trials to obtain average recruitment and derecruitment forces in an effort to minimize variability on a trial-to-trial basis. The microelectrode position was then readjusted, which occasionally included removal of the microelectrode and reinsertion at a new site until the action potentials of presumably a new motor unit could be identified. Individual experiments lasted up to 2 h during which multiple units were tested.
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Traces from bottom to top: isometric force, intramuscular electromyographic signal, discriminated motor unit potentials, and the instantaneous discharge rate of that motor unit. RT1 and DT1, recruitment and derecruitment threshold forces for the unit during phase 1, respectively; RT2 and DT2, recruitment and derecruitment threshold forces during phase 2, respectively; IAI, interactivation interval.
Data analysis
Data were analysed off-line using Spike2 (Cambridge Electronic Design Ltd) and custom-designed software. Motor unit discrimination was necessary to determine recruitment and derecruitment thresholds, and was accomplished using a template-matching algorithm based on waveform shape and amplitude. An event channel that represented the discharges times of accepted action potentials for a motor unit was generated. Based on these discharge times and the detected force, the following measurements were made for each unit during both phase 1 and phase 2 (details of how the measures were obtained are given below): recruitment force, derecruitment force, the rate of change in force at recruitment and derecruitment, firing rates associated with recruitment and derecruitment, peak force, and peak firing rate. All force measurements were made relative to the resting baseline force measured just before phase 1 for each trial. Recruitment force corresponded to the time of the first discharge in a train of spikes during the ascending ramp for which the initial interspike interval was <500 ms. Likewise, derecruitment force corresponded to the time of the last spike generated during the descending ramp and for which the previous interspike interval was <500 ms. The criteria of excluding interspike intervals >500 ms was implemented to avoid assignment of recruitment or derecruitment to sporadically occurring discharges. The average slope of the force signal at recruitment and at derecruitment was calculated over a 1 s epoch centred on the time of recruitment or derecruitment. If, however, the 1 s epoch included the transition from resting force to rising force (at the outset of phase 1), from falling force to rising force (between phase 1 and phase 2), or from falling force to resting force (at the end of phase 2), the measurement window was shifted so as to exclude these transitions in force slope. Recruitment firing rate was calculated from the first four interspike intervals following recruitment, and derecruitment firing rate was calculated from the last four interspike intervals preceding derecruitment. Peak discharge rate was determined as the highest rate for four consecutive interspike intervals, which may or may not have coincided with peak force. Lastly, the interactivation interval (Gorassini et al. 2002b) was calculated as the time between motor unit derecruitment in the first phase and subsequent recruitment of the unit during the second phase.
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For each parameter (except interactivation interval), the mean value was calculated separately for phases 1 and 2 from the multiple trials that were recorded for each motor unit. For all units recorded across subjects but within a muscle, paired t tests were performed to determine if recruitment force was significantly different from derecruitment force, and to determine if there were significant differences in parameters between the two phases. Values are expressed as means (±S.D.) and differences are considered significant at P < 0.05.
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Results
This paper reports the discharge properties during successive triangular isometric force contractions for 74 and 94 motor units in ED and TA, respectively. Weak contraction forces were used in all trials; probably never exceeding 5% of maximum voluntary force for either muscle. Hence, the sample of motor units in this study was probably of the low-threshold type only. On average 4.7 ± 0.8 and 4.7 ± 0.7 trials were recorded for each ED and TA motor unit, respectively. An example of an intramuscular EMG signal from the digit 3 compartment of ED and the corresponding force record during two consecutive triangular force ramps is shown in Fig. 1. While the activities of at least three units were detected in this trial, the analysis was restricted to the one unit that generated sufficient spikes for complete analysis in both phases (i.e. discriminated motor unit, Fig. 1). For this unit, recruitment force was less during phase 1 (0.2 mN) compared to phase 2 (59.4 mN), while derecruitment forces were higher than recruitment forces for both phases (phase 1, 180.5 mN; phase 2, 146.2 mN). For both phases of this sample record, the peak forces were similar (phase 1, 400.4 mN; phase 2, 410.6 mN) as were the peak firing rates (phase 1, 14.7 Hz; phase 2, 16.1 Hz). Furthermore, the firing rates at recruitment were similar for both phases (phase 1, 8.2 Hz; phase 2, 8.4 Hz). The firing rate at derecruitment in phase 1 (7.7 Hz) was modestly higher than that in phase 2 (6.8 Hz), although no systematic difference in the derecruitment firing rate was found between phase 1 and phase 2 for either muscle (Table 1). The average force slope at recruitment in this trial was slightly greater during phase 1 (171.6 mN s–1) compared with phase 2 (151.8 mN s–1) which probably contributed to the lower recruitment force in phase 1 compared with phase 2 (Büdingen and Freund, 1976). Likewise, the average force slope at derecruitment for this trial was greater during phase 1 (–122 mN s–1) compared with phase 2 (–89 mN s–1). The interactivation interval (IAI, Fig. 1) for this trial was 1.7 s.
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Overall, there was no significant difference in the average recruitment force between phases 1 and 2 for the motor units recorded in ED and TA (Figs 2A and 3A, Table 1). The average motor unit recruitment forces for phase 1 and phase 2 in ED were 122 ± 154 and 117 ± 159 mN, respectively, and for TA were 1.3 ± 1.8 and 1.2 ± 1.7 N, respectively. It should be noted, however, that there was a wide range of responses observed across units – some increased, some decreased, and some had little change in recruitment force in phase 2 compared with phase 1. This variability across units depicted in Figs 2A and 3A (and in subsequent figures) underscores the importance of sampling from relatively large numbers of units when attempting to identify general features of motor unit behaviour, and highlights the likelihood that inferences based on modest numbers of observations can be faulty.
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Recruitment thresholds (A), derecruitment thresholds (B), firing rates at recruitment (C), and firing rates at derecruitment (D), for 74 motor units in the middle-finger compartment of extensor digitorum (ED). Each unit is represented by a circle in phase 1 and phase 2; the two circles are connected by a line. Bars represent mean values, and the horizontal line indicates 1 S.D. above the mean. No significant difference in the recruitment or derecruitment thresholds between successive contractions was found. Derecruitment thresholds were significantly larger than the recruitment thresholds for both phases. The firing rate at recruitment for phase 2 (C) was significantly greater than for phase 1.
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Recruitment thresholds (A), derecruitment thresholds (B), firing rates at recruitment (C), and firing rates at derecruitment (D), for 94 motor units in tibialis anterior. Each unit is represented by a circle in phase 1 and phase 2; the two circles are connected by a line. Bars represent mean values, and the horizontal line indicates 1 S.D. above the mean. The data are similar to those for the ED, the only significant finding between the phases was a greater initial discharge rate in phase 2 compared to phase 1. Also consistent with data from the ED was that the force at derecruitment was significantly greater than force at recruitment for both phases.
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At least two additional factors might have influenced the measure of recruitment force in the present experiments. First, the recruitment force of a motor unit can decrease with increased rate of rise of force (Büdingen & Freund, 1976; Romaiguère et al. 1989). For this reason, subjects were instructed to make the force ramps as similar as possible for phases 1 and 2. Indeed, the rate of rise of force for phase 1 was not statistically different to that of phase 2 for ED (Table 1). However, the rate of rise of force at recruitment was greater on average for phase 2 compared with phase 1 for TA (P= 0.01). Furthermore, there was a significant (P= 0.001), albeit weak, negative correlation (R=– 0.33) between rate of rise of force and recruitment threshold for TA units in phase 2. Therefore, had subjects generated lower rates of rise of force during phase 2, then it is likely that the values of recruitment force in phase 2 for TA would have been higher than that reported here.
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A second factor that could have led to an absence of differences in recruitment thresholds between phases 1 and 2 would be an extended interactivation interval. This is because plateau potentials are thought to dissipate in 5–6 s following cessation of motor neurone activity (Svirskis & Hounsgaard, 1997; Bennett et al. 1998; Gorassini et al. 2002b). However, the average interactivation interval was only 3.4 ± 2.1 and 2.4 ± 1.4 s for motor units in ED and TA, respectively. In addition, the peak force and peak firing rate attained in the two phases were not significantly different for either muscle (Table 1). Therefore, no evidence of a ‘warm-up’ effect was observed in either ED or TA under the present experimental conditions.
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Plateau potentials have also been speculated to be manifest as a decreased derecruitment threshold relative to the recruitment threshold (Gorassini et al. 1998;. Heckman and Lee, 1999; Hornby et al. 2002). Because recruitment and derecruitment forces were not significantly different between phase 1 and 2 for motor units in ED (Fig. 2A and B) or TA (Fig. 3A and B), the data from both phases were pooled. Derecruitment threshold was significantly higher than recruitment threshold for both ED (P= 0.02) and TA (P < 0.001) motor units. This result is opposite to that predicted for motor units thought to be exhibiting plateau potentials.
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For trials involving the TA, however, the triangular force ramps were not entirely symmetric. The absolute value of the downward force slope measured at derecruitment was steeper than the upward slope measured at recruitment (Table 1). Abrupt cessation of motor unit activity soon after the onset of the downward phase of a triangular contraction might be associated with an increased rate of force decline. Furthermore, such rapid abeyance of activity could inflate the force value associated with derecruitment compared to recruitment. Therefore, to assess whether differences in force slopes at recruitment and derecruitment in TA might have contributed to differences in recruitment versus derecruitment force, the data were re-analysed using only trials in which the absolute value of the derecruitment force slope was less than or equal to that of the recruitment force slope. For this subset of TA units (n= 35), the average recruitment force (1.7 ± 1.8 N) was significantly (P < 0.001) less than the derecruitment force (4.6 ± 2.8 N). This result is similar to that found when including all TA units. Therefore, inadvertent variation in recruitment and derecruitment force slopes in these experiments did not appear to account for the higher values of force at derecruitment compared to that at recruitment.
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One aspect of motor unit discharge that differed significantly between phases 1 and 2 was that firing rate at recruitment was higher in phase 2 compared to phase 1 (Figs 2C and 3C). This observation was true for both ED (P < 0.001) and TA (P= 0.003). The higher firing rate at recruitment in phase 2 could have been due to the somewhat greater rate of rise of force (i.e. recruitment force slope) during phase 2 compared to phase 1 (Desmedt & Godaux, 1977) (Table 1). However, when all trials in which the rate of rise of force was greater in phase 2 compared to phase 1 were excluded from the analysis, the recruitment firing rates were still significantly greater during phase 2 compared to phase 1 for both ED (P < 0.001) and TA (P= 0.027).
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Another feature of motor unit activity that has been suggested to be associated with the activation of a plateau potential is a higher discharge rate at recruitment compared to derecruitment during triangular force contractions (Gorassini et al. 2002a). No significant differences were found between the discharge rate at recruitment and at derecruitment for phase 1 in either muscle. However, the average discharge rate at recruitment was significantly greater than that at derecruitment in phase 2 for both ED (P= 0.002) and TA (P= 0.004).
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Discussion
Plateau potential activation has been predicted to result in (1) a decrease in motor unit derecruitment force compared to recruitment force, and (2) a progressive decline in motor unit recruitment force during repeated contractions (Gorassini et al. 1998; Bennett et al. 1998; Heckman & Lee, 1999; Hornby et al. 2002). Neither phenomenon was observed for ED or TA motor units in the present experiments during repeated isometric contractions. In fact, the average derecruitment threshold was significantly greater than the mean recruitment threshold in both muscles. Interestingly, however, the firing rates at recruitment in phase 2 were higher than those for phase 1 for both ED and TA. Similarly, in phase 2, firing rates at recruitment were higher than that at derecruitment. Because activation of a plateau potential has been predicted to result in high initial discharge rates (Bennett et al. 2001), such responses observed in phase 2 might indicate that plateau potentials were instigated at some point during the initial (phase 1) contraction.
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Recruitment versus derecruitment thresholds
Our finding that derecruitment thresholds were higher than recruitment thresholds, and that recruitment thresholds were not altered by repeated contractions in finger and ankle muscles, is at variance with previous findings for motor units in wrist extensor muscles (Romaiguère et al. 1993) and elbow flexors (Denier van der Gon et al. 1985; Suzuki et al. 1990). This discrepancy might be due to differences in the extent of monoaminergic innervation supplying different motor neurone pools. On the other hand, differences between previous findings and the current paper could be related to problems associated with the attribution of force measured in human subjects during voluntary contractions to a single muscle. Activity in synergist or antagonist muscles can alter the measured force independently of the force exerted by the muscle within which motor unit activity is recorded. Furthermore, coactivation of antagonist muscles appears to be a fundamental feature of many types of motor tasks, particularly those that are novel or that require a high degree of accuracy (Moore & Marteniuk, 1986; Thoroughman & Shadmehr, 1999; Gribble et al. 2003). For example, during triangular contractions involving increases and decreases in force (as used in the present experiments), or during isotonic contractions involving lifting and lowering a load, there is enhanced activity in antagonist muscles during the force-decreasing or load-lowering phases (De Luca & Mambrito, 1987; Burnett et al. 2000; Laidlaw et al. 2002). Such antagonist muscle activity has been shown to contribute to a reduction in the apparent derecruitment force relative to recruitment force in TA motor units (Patten & Kamen, 2000). Indeed, Patten & Kamen (2000) showed that after 2 weeks of training on a force modulation task, cocontraction of antagonist muscles decreased and derecruitment force was then significantly higher than recruitment force. In the present study, the contribution of antagonist muscles to the measured force was minimized by holding them at shortened lengths. Therefore, our force measures could be more confidently attributed to the activity of the muscles from which we made our motor unit recordings.
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Furthermore, on theoretical grounds, it is difficult to explain how plateau potential activation could result in a change in force threshold even if it were possible to measure the force of a single muscle in isolation. Muscle force is the outcome, and not the cause, of motor unit activity. The recruitment force of a unit is nothing more than the sum of the forces developed by the other units activated prior to the unit under study. Consequently, a decline in the recruitment force of a motor unit during a pair of repeated contractions would require that (1) the intrinsic force capacity of active motor units decrease from the first to the second contraction; (2) fewer motor units be recruited in the second contraction, which necessarily implies a change in recruitment order; or (3) the firing rates of the motor units decrease in the second contraction. There is little evidence to support these requirements. Indeed (1) motor unit force is more likely to increase than decreases during the type of brief, low-force contractions typically used to study motor unit recruitment (De Luca et al. 1996; Carpentier et al. 2001); (2) the sequence of motor unit recruitment during isometric contractions has repeatedly been demonstrated to be stable (Tanji & Kato, 1973; Desmedt & Godaux, 1979a,b; De Luca et al. 1982; Thomas et al. 1987; De Luca & Mambrito, 1987; Clark et al. 1993; Adam & De Luca, 2003); and (3) the firing rates of motor units when recruited during the second contraction in the present experiments were higher than during the first contraction (Figs 2C and 3C). Therefore, while activation of plateau potentials should result in less excitatory synaptic input required to recruit motor neurones, it seems doubtful that such an effect would manifest itself as a reduction in the muscle force at which motor units are recruited.
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As anticipated from the relatively sluggish mechanical properties of skeletal muscle, derecruitment force was greater than recruitment force. This expectation arises because of the time lag between the detection of a motor unit action potential and the full expression of motor unit force (De Luca et al. 1982). Conceptually, therefore, the muscle force associated with the detection of the first discharge of a motor unit (i.e. the recruitment force) is that due to the activities of all the previously active units. On the other hand, the muscle force coinciding with the cessation of activity in a motor unit results from the forces of the other active units, plus the force contributed by the unit itself. Furthermore, the muscle force associated with abeyance of activity in a unit will also likely include the forces contributed by other higher threshold units because their force persists for a few hundred milliseconds following their cessation of activity.
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Other criteria for identifying plateau potentials
Besides changes in the force at recruitment and derecruitment, other suggested evidence of plateau potential activity is the sustained discharge of motor units that outlast an excitatory stimulus (Crone et al. 1988; Kiehn & Eken, 1997; Gorassini et al. 1998; Bennett et al. 2001). For example, human TA and triceps surae can exhibit sustained contractions following the cessation of high-frequency electrical stimulation (Collins et al. 2001, 2002; Nozaki et al. 2003). Interestingly, such findings are reminiscent of those described by Sherrington and colleagues in the early part of the 20th century in which reflex responses were found to greatly outlast the triggering stimulus (Sherrington, 1906a). These persistent reflex responses, referred to as ‘after-discharges’, were attributed to an unknown and enduring ‘central excitatory state’ (Creed et al. 1932). Moreover, such long-lasting activity occurred in both acute and in chronically spinalized animals (Sherrington, 1906a,b, 1909, 1910), suggesting that prolonged responses to brief stimuli can occur in the absence of descending monoaminergic inputs. Subsequent observations of such sustained responses after the removal of a stimulus were attributed to the presence of complex interspinal pathways or to reverberating spinal circuits (Forbes, 1922; Lloyd, 1972; Kanda, 1972; Hultborn et al. 1975; Rymer & Hasan, 1981; Carp & Rymer, 1986).
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The presence of plateau potentials has also been investigated by examining the recruitment and derecruitment thresholds of a test unit relative to the firing rate of a lower-threshold control unit (Kiehn & Eken, 1997; Gorassini et al. 1998; Bennett et al. 2001; Gorassini et al. 2002a,b). In such a paired motor-unit recording approach, firing rate of the control unit is used as a monitor of the common synaptic input to the two neurones (Kiehn & Eken, 1997). Therefore, if the firing rate of the control unit (representing synaptic input) is lower when the test unit is derecruited compared to when the test unit is recruited, then this is interpreted to indicate that less ionotropic-mediated synaptic current is needed to maintain the activity of the test unit relative to that needed to recruit it intially. Such maintenance of discharge in the presence of lowered synaptic current is thought to be accounted for by the activation of a persistent inward currents (Bennett et al. 2001; Gorassini et al. 2002a,b). Several caveats related to this approach, however, have been outlined (Kiehn & Eken, 1997; Bennett et al. 2001). Most critical is that associated with firing rate saturation (e.g. Johns & Fuglevand, 2004) which limits the use of control-unit discharge as a general indicator of synaptic input. Indeed, evidence that control units did not respond to increases in synaptic drive is seen from the absence of increased discharge rate of control units during tendon vibration (Fig. 1 in Gorassini et al. 2002a); and during substantial increases in voluntary force (Fig. 2 in Gorassini et al. 2002a; Fig. 5 in Gorassini et al. 2002b; Fig. 12 in Heckman et al. 2005). Because a main assumption underlying the paired motor unit recording approach is that ‘the firing rate of the control motor unit was a sensitive and linear indicator of the net excitatory synaptic drive’ (Gorassini et al. 2002a), and because firing rate saturation can be a prevalent phenomenon, the utility of this method to characterize synaptic input requires further consideration.
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Rapid deactivation of plateau potentials
It is also possible in the present experiments that plateau potentials could have been instigated during the rising portion of the triangular contractions but actively extinguished during the falling phase. Indeed, a characteristic feature of plateau potentials is that they can be readily interrupted by brief injection of hyperpolarizing current or by synaptic inhibition (Hounsgaard et al. 1988; Kuo et al. 2003). Furthermore, voluntary muscle relaxation associated with the falling phase of triangular contractions might occur not only because of a progressive withdrawal of descending excitatory drive, but also because of concomitant engagement of descending pathways that inhibit motor neurones (Jankowska et al. 1976). Such synaptic inhibition might curtail plateau potentials initiated during the rising phase thereby eliminating evidence of plateau potentials during the falling phase. This is a possibility that cannot be discounted by the present experiments.
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Physiological conditions for plateau potentials
Ultimately, there is little doubt that the machinery for monoamine- and other neuromodulator-mediated persistent inward currents is a prominent feature of mammalian spinal neurones (Alvarez et al. 1998; Rekling et al. 2000; Hochman et al. 2001; Heckman et al. 2003) and that plateau potentials and ‘warm up’ effects can occur as evidenced by isolated studies. A more pertinent issue, however, relates to the physiological conditions under which these phenomena are expressed. In the present study, we found little evidence of a plateau potential meditated ‘warm up’ of motor units controlling either a hand or a postural muscle during weak isometric contractions based on previously proposed criteria. It is possible, as we have suggested above, that these criteria may not always be suitable for determining the activation of a plateau potential. On the other hand, it is also possible that for most types of ‘normal’ motor behaviours, motor neurones may operate in a milieu consisting of relatively low concentrations of monoamines. Microdialysis of monoamine concentrations in the ventral horn of the lumbar spinal cord of decerbrate cats (Lai et al. 2001) yield quite modest levels of serotonin (1–10 pM, Y.-Y. Lai, personal communication), several orders of magnitude less than that typically used to elicit plateau potentials in motor neurones during in vitro studies (e.g. 10–100 mM, Bennett et al. 2001; Perrier & Tresch, 2005). Furthermore, the concentration of extracellular serotonin in the ventral horn of freely behaving rats appears to decrease during exercise (treadmill running) compared to that measured at rest (Gerin & Privat, 1998).
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Perhaps then, it is only under ‘fight or flight’ conditions that there is sufficient monoamine input to the spinal cord to activate plateau potentials and thereby augment motor unit activity in situations of high stress or arousal (Heckman et al. 2003). It seems premature therefore to conclude that the monoaminergic-mediated persistent inward current associated with plateau potentials ‘provides the majority of current to drive normal recruitment and rate modulation’ (Heckman et al. 2005). The question of the physiological role of plateau potentials must remain open until methods are developed that allow monoamine concentration in the spinal cord to be readily monitored and plateau potentials to be unequivocally identified in awake behaving animals.
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Abstract
Spinal motor neurones can exhibit sustained depolarization in the absence of maintained synaptic or injected current. This phenomenon, referred to as a plateau potential, is due to the activation of monoamine-dependent persistent inward currents. Accordingly, activation of a plateau potential should result in a decrease in the excitatory synaptic drive required to activate a motor unit. This, in turn, has been suggested to cause a progressive decline in the muscle force at which motor units are recruited during repeated voluntary contractions. Such a progressive decrease in threshold force associated with preceding activation of a plateau potential is referred to as ‘warm up’. Furthermore, activation of a plateau potential is thought to manifest itself as a decrease in the derecruitment force compared to recruitment force. Multiple muscles, however, can contribute to the detected force and their relative contributions may vary over time, which could confound measures of recruitment and derecruitment force. Therefore, the purpose of this study was to compare the recruitment and derecruitment forces of single motor units in the human extensor digitorum and tibialis anterior during repetitive triangular-force contractions in which the contributions of other muscles had been minimized. In both muscles, we found that the recruitment thresholds of single motor units were unchanged during repeated contractions, and that the derecruitment force was consistently greater than the recruitment force. These results suggest either that plateau potentials were not engaged (or were rapidly extinguished) under these experimental conditions or that changes in recruitment and derecruitment force are not suitable criteria for detecting them.
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Introduction
A plateau potential is a sustained depolarization that can be maintained for several seconds after synaptic excitation (or intracellular current injection) has been reduced or removed (Hounsgaard et al. 1984, 1988). In vertebrate motor neurones, the sustained depolarization appears to be caused by the activation of voltage-gated, slowly inactivating inward currents (referred to as persistent inward currents), primarily those mediated by Ca2+ entering through L-type channels (Hounsgaard & Kiehn, 1985, 1989;. Hounsgaard & Mintz, 1988; Perrier & Hounsgaard, 2003). In order for these channels to be activated by depolarization (10–30 mV from the resting potential, Alaburda et al. 2002), they first must be enabled by an intracellular biochemical cascade that is instigated by the binding of various neuromodulators (Rekling et al. 2000), such as monoamines to dendritic metabotropic receptors (Perrier et al. 2000; Perrier & Hounsgaard, 2003). Axons projecting from nuclei in the brain stem provide the primary source of monoamines (e.g. as serotonin and noradrenaline) to spinal neurones through direct synaptic contacts (Alvarez et al. 1998; Maxwell et al. 2000). Indeed, electrical stimulation of the raphe nucleus in isolated brain-stem–spinal-cord preparations has been shown to promote plateau potentials in turtle spinal motor neurones (Perrier and Delgado-Lezama, 2005). Furthermore, monoamine-dependent persistent inward currents and associated plateau potentials have been demonstrated in spinal motor neurones of reduced preparations in a variety of other vertebrate species (see reviews by Kiehn, 1991; Hultborn & Kiehn, 1992; Hornby et al. 2002; Heckman et al. 2003, 2005).
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The possible functional roles of plateau potentials, however, remain a matter of debate (Hornby et al. 2001). To resolve this issue, it is necessary to determine whether, and under what conditions, plateau potentials are activated in intact animals. An unequivocal demonstration of plateau-potential expression requires that the magnitude of synaptic input be known. This factor represents a largely insurmountable obstacle in attempts to identify plateau potentials in intact animals. Nevertheless, a number of criteria have been proposed as evidence for activation of plateau potentials based on the discharge behaviour of motor units recorded in intact humans during voluntary contractions (Kiehn & Eken, 1997; Heckman & Lee, 1999; Gorassini et al. 2002a,b; Hornby et al. 2002). In particular, it has been suggested that activation of a plateau potential during a contraction should diminish the excitatory synaptic drive needed subsequently to recruit (or de-recruit) motor neurones. Such lowering in threshold is thought to manifest itself in motor unit recordings as a decrease in derecruitment force compared to recruitment force, and as a progressive decline in recruitment force during repeated contractions (Gorassini et al. 1998; Bennett et al. 1998; Heckman & Lee, 1999; Hornby et al. 2002). Other evidence for threshold-lowering associated with activation of plateau potentials has been inferred based on the relative change in firing rates of control units (rather than on muscle force) at the times of recruitment and derecruitment of simultaneously recorded test units (Kiehn & Eken, 1997; Gorassini et al. 1998, 2002a,b; Bennett et al. 2001; see Discussion). The reduction in threshold (measured in terms of force or control-unit firing rate) associated with the preceding activation of a plateau potential is referred to as ‘warm up’ (Bennett et al. 1998).
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An alternative explanation for ‘warm up’, as evidenced by a reduction in threshold force, is that during triangular ramp contractions involving precise increases and decreases in force, antagonist muscles may be slightly more active during the decreasing force phase (De Luca & Mambrito, 1987). Such antagonist muscle activity would reduce the net torque at the joint and thereby lower the measured force. Therefore, activity in antagonist muscles can give rise to the appearance of decreased derecruitment thresholds (Patten & Kamen, 2000). Furthermore, such antagonist activity might carry over into an immediately following ramp contraction and cause an apparent drop in recruitment threshold.
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The purpose of the present study therefore was to compare recruitment and derecruitment thresholds of single motor units in extensor digitorum (ED), a muscle involved in controlling the fingers, and tibialis anterior (TA), a postural muscle, during repetitive contractions in which the contributions of antagonistic muscles had been minimized. This was accomplished by positioning the joints of the hand and ankle in such a way so as to hold antagonistic muscles at short lengths and thereby undermine their ability to generate force. Consequently, ‘warm-up’-related changes in thresholds of recruitment or derecruitment, if observed, could be more confidently attributed to plateau-potential mediated effects rather than as a result of activation of antagonist muscles.
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Methods
A total of 27 experiments were performed in 18 healthy human volunteers (nine women, nine men, ages 21–43 years). The experimental procedures were approved by the Human Investigation Committee at the University of Arizona. All subjects gave their informed consent to participate in the study. Fifteen experiments were performed on the compartment of ED that controls digit 3 of the right hand, and 12 experiments were carried out on the TA of the right leg. The ED was selected for study because it has virtually no synergists for extension of the metacarpalphalangeal (MCP) joint of digit 3. The TA was selected because motor units in this muscle have been shown previously to exhibit responses considered to be indicative of plateau potentials (Kiehn & Eken, 1997; Gorassini et al. 1998, 2002a,b; Collins et al. 2002).
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Experimental set-up
Details of the experimental arrangement for experiments involving the digit 3 compartment of ED have been provided previously (Keen & Fuglevand, 2003). Briefly, subjects were seated comfortably in a dental chair with their right elbow and wrist supported and immobilized. The elbow was flexed at approximately 30 deg from full extension, the wrist was flexed about 45 deg, and the hand was orientated midway between fully supinated and fully pronated with the thumb pointing upwards. The MCP joints were maintained in a fully flexed position (90 deg of flexion) by metal cuffs around the proximal interphalangeal joints that were attached to separate force transducers via light-weight cables. With this hand position, the finger flexors were held at shortened lengths, which minimized their ability to generate force. In a separate series of experiments carried out in five subjects, the mean (±S.D.) maximum voluntary contraction (MVC) force for digit 3 flexion in this shortened configuration was 38 ± 21% of that generated when the MCP joint was held in a neutral (180 deg) position.
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For experiments that examined motor units in TA, subjects were comfortably seated in a dental chair with their knee flexed by about 30 deg. The foot was secured to a cantilevered metal foot plate with a Velcro strap and the heel of the fool rested in a thermoplastic cup. A strain-gauge transducer was attached to the foot plate to measure dorsiflexion force. The foot plate was mounted on an adjustable platform that was tilted individually for each subject in order to hold the ankle joint in full plantar flexion. This greatly reduced the capacity of the plantar flexor muscles to exert force. In separate set of experiments carried out in four subjects, the MVC force associated with plantar flexion in this position was 18 ± 10% of that exerted when the ankle was held in a neutral orientation (i.e. 90 deg angle between plantar surface of foot and longitudinal axis of tibia).
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Force and EMG recording
Extension forces of the digits were measured by four force transducers (range of 0–5 N and sensitivity of 780 mN mV–1; Grass Instruments, Warwick, Rhode Island, USA); however, only the force recordings from digit 3 were analysed. The force transducers were mounted in a custom-built manipulandum that allowed each transducer to be aligned with the proximal interphalangeal joint of the appropriate finger. A less sensitive force transducer (range of 0–400 N and sensitivity of 56 N mV–1) was used to measure foot dorsiflexion force for the TA experiments. The force signals from ED or TA were amplified (x1000) and displayed on an oscilloscope and a computer monitor.
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Motor unit action potentials were recorded with sterilized tungsten microelectrodes inserted into the digit 3 compartment of ED or into TA (Frederick Haer and Co. Bowdoinham, Maine, USA; 1–5 μm tip diameter, 5–10 μm uninsulated length, 250 μm shaft diameter, 200 k impedance at 1000 Hz after insertion). Weak electrical stimulation was used initially to verify microelectrode placement in the digit 3 compartment of ED based on the magnitude of the force evoked by the stimulation on digit 3 compared with the other fingers (Keen & Fuglevand, 2003). A surface electrode (4 mm diameter, Ag–AgCl) attached to the skin overlying the radius served as the anode during stimulation. The same electrode served as the reference electrode during motor unit recording in ED. For TA experiments, a surface electrode placed over the tibia served as the reference electrode. The intramuscular electromyographic (EMG) signals were differentially amplified (x1000), band pass filtered (0.3–3 kHz) (Grass Instruments), displayed on an oscilloscope, and routed to an audio amplifier. Force and EMG signals were digitized at a rate of approximately 2 and 20 kHz, respectively (Cambridge Electronic Design Ltd, Cambridge, UK).
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Protocol
Initially, subjects performed weak isometric contractions of ED or TA by attempting to extend digit 3 or dorsiflex the foot, respectively. During these contractions, the microelectrode was manipulated until the action potentials of a motor unit could be clearly identified. Once the discharge potentials of at least one motor unit could be identified from the intramuscular EMG signals, subjects performed two consecutive triangular isometric force ramps (referred to as phase 1 and phase 2 of the trial) (Fig. 1). Using visual feedback of force on a computer display, subjects attempted to steadily increase and then decrease finger extension or foot dorsiflexion force and to generate the same force profile for both phases. Subjects were instructed to keep the limb relaxed prior to the onset of the contraction, and then to increase the force during the ramp beyond that needed to recruit the unit under study, but to not exceed force levels that might lead to excessive activation of several other units. Therefore, the absolute force exerted during the triangular force ramps varied from one unit to another. After the two phases, subjects rested for approximately 30 s before performing another trial of two successive triangular force ramps. This duration (30 s) of rest period was chosen because plateau potentials are thought to dissipate within 5–6 s following a contraction (Svirskis & Hounsgaard, 1997; Bennett et al. 1998; Gorassini et al. 2002b). Consequently, it was assumed that following 30 s of rest and immediately prior to the outset of each trial, plateau potentials were not present in motor neurones. Each unit was tested during between three and five trials to obtain average recruitment and derecruitment forces in an effort to minimize variability on a trial-to-trial basis. The microelectrode position was then readjusted, which occasionally included removal of the microelectrode and reinsertion at a new site until the action potentials of presumably a new motor unit could be identified. Individual experiments lasted up to 2 h during which multiple units were tested.
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Traces from bottom to top: isometric force, intramuscular electromyographic signal, discriminated motor unit potentials, and the instantaneous discharge rate of that motor unit. RT1 and DT1, recruitment and derecruitment threshold forces for the unit during phase 1, respectively; RT2 and DT2, recruitment and derecruitment threshold forces during phase 2, respectively; IAI, interactivation interval.
Data analysis
Data were analysed off-line using Spike2 (Cambridge Electronic Design Ltd) and custom-designed software. Motor unit discrimination was necessary to determine recruitment and derecruitment thresholds, and was accomplished using a template-matching algorithm based on waveform shape and amplitude. An event channel that represented the discharges times of accepted action potentials for a motor unit was generated. Based on these discharge times and the detected force, the following measurements were made for each unit during both phase 1 and phase 2 (details of how the measures were obtained are given below): recruitment force, derecruitment force, the rate of change in force at recruitment and derecruitment, firing rates associated with recruitment and derecruitment, peak force, and peak firing rate. All force measurements were made relative to the resting baseline force measured just before phase 1 for each trial. Recruitment force corresponded to the time of the first discharge in a train of spikes during the ascending ramp for which the initial interspike interval was <500 ms. Likewise, derecruitment force corresponded to the time of the last spike generated during the descending ramp and for which the previous interspike interval was <500 ms. The criteria of excluding interspike intervals >500 ms was implemented to avoid assignment of recruitment or derecruitment to sporadically occurring discharges. The average slope of the force signal at recruitment and at derecruitment was calculated over a 1 s epoch centred on the time of recruitment or derecruitment. If, however, the 1 s epoch included the transition from resting force to rising force (at the outset of phase 1), from falling force to rising force (between phase 1 and phase 2), or from falling force to resting force (at the end of phase 2), the measurement window was shifted so as to exclude these transitions in force slope. Recruitment firing rate was calculated from the first four interspike intervals following recruitment, and derecruitment firing rate was calculated from the last four interspike intervals preceding derecruitment. Peak discharge rate was determined as the highest rate for four consecutive interspike intervals, which may or may not have coincided with peak force. Lastly, the interactivation interval (Gorassini et al. 2002b) was calculated as the time between motor unit derecruitment in the first phase and subsequent recruitment of the unit during the second phase.
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For each parameter (except interactivation interval), the mean value was calculated separately for phases 1 and 2 from the multiple trials that were recorded for each motor unit. For all units recorded across subjects but within a muscle, paired t tests were performed to determine if recruitment force was significantly different from derecruitment force, and to determine if there were significant differences in parameters between the two phases. Values are expressed as means (±S.D.) and differences are considered significant at P < 0.05.
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Results
This paper reports the discharge properties during successive triangular isometric force contractions for 74 and 94 motor units in ED and TA, respectively. Weak contraction forces were used in all trials; probably never exceeding 5% of maximum voluntary force for either muscle. Hence, the sample of motor units in this study was probably of the low-threshold type only. On average 4.7 ± 0.8 and 4.7 ± 0.7 trials were recorded for each ED and TA motor unit, respectively. An example of an intramuscular EMG signal from the digit 3 compartment of ED and the corresponding force record during two consecutive triangular force ramps is shown in Fig. 1. While the activities of at least three units were detected in this trial, the analysis was restricted to the one unit that generated sufficient spikes for complete analysis in both phases (i.e. discriminated motor unit, Fig. 1). For this unit, recruitment force was less during phase 1 (0.2 mN) compared to phase 2 (59.4 mN), while derecruitment forces were higher than recruitment forces for both phases (phase 1, 180.5 mN; phase 2, 146.2 mN). For both phases of this sample record, the peak forces were similar (phase 1, 400.4 mN; phase 2, 410.6 mN) as were the peak firing rates (phase 1, 14.7 Hz; phase 2, 16.1 Hz). Furthermore, the firing rates at recruitment were similar for both phases (phase 1, 8.2 Hz; phase 2, 8.4 Hz). The firing rate at derecruitment in phase 1 (7.7 Hz) was modestly higher than that in phase 2 (6.8 Hz), although no systematic difference in the derecruitment firing rate was found between phase 1 and phase 2 for either muscle (Table 1). The average force slope at recruitment in this trial was slightly greater during phase 1 (171.6 mN s–1) compared with phase 2 (151.8 mN s–1) which probably contributed to the lower recruitment force in phase 1 compared with phase 2 (Büdingen and Freund, 1976). Likewise, the average force slope at derecruitment for this trial was greater during phase 1 (–122 mN s–1) compared with phase 2 (–89 mN s–1). The interactivation interval (IAI, Fig. 1) for this trial was 1.7 s.
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Overall, there was no significant difference in the average recruitment force between phases 1 and 2 for the motor units recorded in ED and TA (Figs 2A and 3A, Table 1). The average motor unit recruitment forces for phase 1 and phase 2 in ED were 122 ± 154 and 117 ± 159 mN, respectively, and for TA were 1.3 ± 1.8 and 1.2 ± 1.7 N, respectively. It should be noted, however, that there was a wide range of responses observed across units – some increased, some decreased, and some had little change in recruitment force in phase 2 compared with phase 1. This variability across units depicted in Figs 2A and 3A (and in subsequent figures) underscores the importance of sampling from relatively large numbers of units when attempting to identify general features of motor unit behaviour, and highlights the likelihood that inferences based on modest numbers of observations can be faulty.
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Recruitment thresholds (A), derecruitment thresholds (B), firing rates at recruitment (C), and firing rates at derecruitment (D), for 74 motor units in the middle-finger compartment of extensor digitorum (ED). Each unit is represented by a circle in phase 1 and phase 2; the two circles are connected by a line. Bars represent mean values, and the horizontal line indicates 1 S.D. above the mean. No significant difference in the recruitment or derecruitment thresholds between successive contractions was found. Derecruitment thresholds were significantly larger than the recruitment thresholds for both phases. The firing rate at recruitment for phase 2 (C) was significantly greater than for phase 1.
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Recruitment thresholds (A), derecruitment thresholds (B), firing rates at recruitment (C), and firing rates at derecruitment (D), for 94 motor units in tibialis anterior. Each unit is represented by a circle in phase 1 and phase 2; the two circles are connected by a line. Bars represent mean values, and the horizontal line indicates 1 S.D. above the mean. The data are similar to those for the ED, the only significant finding between the phases was a greater initial discharge rate in phase 2 compared to phase 1. Also consistent with data from the ED was that the force at derecruitment was significantly greater than force at recruitment for both phases.
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At least two additional factors might have influenced the measure of recruitment force in the present experiments. First, the recruitment force of a motor unit can decrease with increased rate of rise of force (Büdingen & Freund, 1976; Romaiguère et al. 1989). For this reason, subjects were instructed to make the force ramps as similar as possible for phases 1 and 2. Indeed, the rate of rise of force for phase 1 was not statistically different to that of phase 2 for ED (Table 1). However, the rate of rise of force at recruitment was greater on average for phase 2 compared with phase 1 for TA (P= 0.01). Furthermore, there was a significant (P= 0.001), albeit weak, negative correlation (R=– 0.33) between rate of rise of force and recruitment threshold for TA units in phase 2. Therefore, had subjects generated lower rates of rise of force during phase 2, then it is likely that the values of recruitment force in phase 2 for TA would have been higher than that reported here.
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A second factor that could have led to an absence of differences in recruitment thresholds between phases 1 and 2 would be an extended interactivation interval. This is because plateau potentials are thought to dissipate in 5–6 s following cessation of motor neurone activity (Svirskis & Hounsgaard, 1997; Bennett et al. 1998; Gorassini et al. 2002b). However, the average interactivation interval was only 3.4 ± 2.1 and 2.4 ± 1.4 s for motor units in ED and TA, respectively. In addition, the peak force and peak firing rate attained in the two phases were not significantly different for either muscle (Table 1). Therefore, no evidence of a ‘warm-up’ effect was observed in either ED or TA under the present experimental conditions.
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Plateau potentials have also been speculated to be manifest as a decreased derecruitment threshold relative to the recruitment threshold (Gorassini et al. 1998;. Heckman and Lee, 1999; Hornby et al. 2002). Because recruitment and derecruitment forces were not significantly different between phase 1 and 2 for motor units in ED (Fig. 2A and B) or TA (Fig. 3A and B), the data from both phases were pooled. Derecruitment threshold was significantly higher than recruitment threshold for both ED (P= 0.02) and TA (P < 0.001) motor units. This result is opposite to that predicted for motor units thought to be exhibiting plateau potentials.
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For trials involving the TA, however, the triangular force ramps were not entirely symmetric. The absolute value of the downward force slope measured at derecruitment was steeper than the upward slope measured at recruitment (Table 1). Abrupt cessation of motor unit activity soon after the onset of the downward phase of a triangular contraction might be associated with an increased rate of force decline. Furthermore, such rapid abeyance of activity could inflate the force value associated with derecruitment compared to recruitment. Therefore, to assess whether differences in force slopes at recruitment and derecruitment in TA might have contributed to differences in recruitment versus derecruitment force, the data were re-analysed using only trials in which the absolute value of the derecruitment force slope was less than or equal to that of the recruitment force slope. For this subset of TA units (n= 35), the average recruitment force (1.7 ± 1.8 N) was significantly (P < 0.001) less than the derecruitment force (4.6 ± 2.8 N). This result is similar to that found when including all TA units. Therefore, inadvertent variation in recruitment and derecruitment force slopes in these experiments did not appear to account for the higher values of force at derecruitment compared to that at recruitment.
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One aspect of motor unit discharge that differed significantly between phases 1 and 2 was that firing rate at recruitment was higher in phase 2 compared to phase 1 (Figs 2C and 3C). This observation was true for both ED (P < 0.001) and TA (P= 0.003). The higher firing rate at recruitment in phase 2 could have been due to the somewhat greater rate of rise of force (i.e. recruitment force slope) during phase 2 compared to phase 1 (Desmedt & Godaux, 1977) (Table 1). However, when all trials in which the rate of rise of force was greater in phase 2 compared to phase 1 were excluded from the analysis, the recruitment firing rates were still significantly greater during phase 2 compared to phase 1 for both ED (P < 0.001) and TA (P= 0.027).
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Another feature of motor unit activity that has been suggested to be associated with the activation of a plateau potential is a higher discharge rate at recruitment compared to derecruitment during triangular force contractions (Gorassini et al. 2002a). No significant differences were found between the discharge rate at recruitment and at derecruitment for phase 1 in either muscle. However, the average discharge rate at recruitment was significantly greater than that at derecruitment in phase 2 for both ED (P= 0.002) and TA (P= 0.004).
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Discussion
Plateau potential activation has been predicted to result in (1) a decrease in motor unit derecruitment force compared to recruitment force, and (2) a progressive decline in motor unit recruitment force during repeated contractions (Gorassini et al. 1998; Bennett et al. 1998; Heckman & Lee, 1999; Hornby et al. 2002). Neither phenomenon was observed for ED or TA motor units in the present experiments during repeated isometric contractions. In fact, the average derecruitment threshold was significantly greater than the mean recruitment threshold in both muscles. Interestingly, however, the firing rates at recruitment in phase 2 were higher than those for phase 1 for both ED and TA. Similarly, in phase 2, firing rates at recruitment were higher than that at derecruitment. Because activation of a plateau potential has been predicted to result in high initial discharge rates (Bennett et al. 2001), such responses observed in phase 2 might indicate that plateau potentials were instigated at some point during the initial (phase 1) contraction.
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Recruitment versus derecruitment thresholds
Our finding that derecruitment thresholds were higher than recruitment thresholds, and that recruitment thresholds were not altered by repeated contractions in finger and ankle muscles, is at variance with previous findings for motor units in wrist extensor muscles (Romaiguère et al. 1993) and elbow flexors (Denier van der Gon et al. 1985; Suzuki et al. 1990). This discrepancy might be due to differences in the extent of monoaminergic innervation supplying different motor neurone pools. On the other hand, differences between previous findings and the current paper could be related to problems associated with the attribution of force measured in human subjects during voluntary contractions to a single muscle. Activity in synergist or antagonist muscles can alter the measured force independently of the force exerted by the muscle within which motor unit activity is recorded. Furthermore, coactivation of antagonist muscles appears to be a fundamental feature of many types of motor tasks, particularly those that are novel or that require a high degree of accuracy (Moore & Marteniuk, 1986; Thoroughman & Shadmehr, 1999; Gribble et al. 2003). For example, during triangular contractions involving increases and decreases in force (as used in the present experiments), or during isotonic contractions involving lifting and lowering a load, there is enhanced activity in antagonist muscles during the force-decreasing or load-lowering phases (De Luca & Mambrito, 1987; Burnett et al. 2000; Laidlaw et al. 2002). Such antagonist muscle activity has been shown to contribute to a reduction in the apparent derecruitment force relative to recruitment force in TA motor units (Patten & Kamen, 2000). Indeed, Patten & Kamen (2000) showed that after 2 weeks of training on a force modulation task, cocontraction of antagonist muscles decreased and derecruitment force was then significantly higher than recruitment force. In the present study, the contribution of antagonist muscles to the measured force was minimized by holding them at shortened lengths. Therefore, our force measures could be more confidently attributed to the activity of the muscles from which we made our motor unit recordings.
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Furthermore, on theoretical grounds, it is difficult to explain how plateau potential activation could result in a change in force threshold even if it were possible to measure the force of a single muscle in isolation. Muscle force is the outcome, and not the cause, of motor unit activity. The recruitment force of a unit is nothing more than the sum of the forces developed by the other units activated prior to the unit under study. Consequently, a decline in the recruitment force of a motor unit during a pair of repeated contractions would require that (1) the intrinsic force capacity of active motor units decrease from the first to the second contraction; (2) fewer motor units be recruited in the second contraction, which necessarily implies a change in recruitment order; or (3) the firing rates of the motor units decrease in the second contraction. There is little evidence to support these requirements. Indeed (1) motor unit force is more likely to increase than decreases during the type of brief, low-force contractions typically used to study motor unit recruitment (De Luca et al. 1996; Carpentier et al. 2001); (2) the sequence of motor unit recruitment during isometric contractions has repeatedly been demonstrated to be stable (Tanji & Kato, 1973; Desmedt & Godaux, 1979a,b; De Luca et al. 1982; Thomas et al. 1987; De Luca & Mambrito, 1987; Clark et al. 1993; Adam & De Luca, 2003); and (3) the firing rates of motor units when recruited during the second contraction in the present experiments were higher than during the first contraction (Figs 2C and 3C). Therefore, while activation of plateau potentials should result in less excitatory synaptic input required to recruit motor neurones, it seems doubtful that such an effect would manifest itself as a reduction in the muscle force at which motor units are recruited.
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As anticipated from the relatively sluggish mechanical properties of skeletal muscle, derecruitment force was greater than recruitment force. This expectation arises because of the time lag between the detection of a motor unit action potential and the full expression of motor unit force (De Luca et al. 1982). Conceptually, therefore, the muscle force associated with the detection of the first discharge of a motor unit (i.e. the recruitment force) is that due to the activities of all the previously active units. On the other hand, the muscle force coinciding with the cessation of activity in a motor unit results from the forces of the other active units, plus the force contributed by the unit itself. Furthermore, the muscle force associated with abeyance of activity in a unit will also likely include the forces contributed by other higher threshold units because their force persists for a few hundred milliseconds following their cessation of activity.
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Other criteria for identifying plateau potentials
Besides changes in the force at recruitment and derecruitment, other suggested evidence of plateau potential activity is the sustained discharge of motor units that outlast an excitatory stimulus (Crone et al. 1988; Kiehn & Eken, 1997; Gorassini et al. 1998; Bennett et al. 2001). For example, human TA and triceps surae can exhibit sustained contractions following the cessation of high-frequency electrical stimulation (Collins et al. 2001, 2002; Nozaki et al. 2003). Interestingly, such findings are reminiscent of those described by Sherrington and colleagues in the early part of the 20th century in which reflex responses were found to greatly outlast the triggering stimulus (Sherrington, 1906a). These persistent reflex responses, referred to as ‘after-discharges’, were attributed to an unknown and enduring ‘central excitatory state’ (Creed et al. 1932). Moreover, such long-lasting activity occurred in both acute and in chronically spinalized animals (Sherrington, 1906a,b, 1909, 1910), suggesting that prolonged responses to brief stimuli can occur in the absence of descending monoaminergic inputs. Subsequent observations of such sustained responses after the removal of a stimulus were attributed to the presence of complex interspinal pathways or to reverberating spinal circuits (Forbes, 1922; Lloyd, 1972; Kanda, 1972; Hultborn et al. 1975; Rymer & Hasan, 1981; Carp & Rymer, 1986).
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The presence of plateau potentials has also been investigated by examining the recruitment and derecruitment thresholds of a test unit relative to the firing rate of a lower-threshold control unit (Kiehn & Eken, 1997; Gorassini et al. 1998; Bennett et al. 2001; Gorassini et al. 2002a,b). In such a paired motor-unit recording approach, firing rate of the control unit is used as a monitor of the common synaptic input to the two neurones (Kiehn & Eken, 1997). Therefore, if the firing rate of the control unit (representing synaptic input) is lower when the test unit is derecruited compared to when the test unit is recruited, then this is interpreted to indicate that less ionotropic-mediated synaptic current is needed to maintain the activity of the test unit relative to that needed to recruit it intially. Such maintenance of discharge in the presence of lowered synaptic current is thought to be accounted for by the activation of a persistent inward currents (Bennett et al. 2001; Gorassini et al. 2002a,b). Several caveats related to this approach, however, have been outlined (Kiehn & Eken, 1997; Bennett et al. 2001). Most critical is that associated with firing rate saturation (e.g. Johns & Fuglevand, 2004) which limits the use of control-unit discharge as a general indicator of synaptic input. Indeed, evidence that control units did not respond to increases in synaptic drive is seen from the absence of increased discharge rate of control units during tendon vibration (Fig. 1 in Gorassini et al. 2002a); and during substantial increases in voluntary force (Fig. 2 in Gorassini et al. 2002a; Fig. 5 in Gorassini et al. 2002b; Fig. 12 in Heckman et al. 2005). Because a main assumption underlying the paired motor unit recording approach is that ‘the firing rate of the control motor unit was a sensitive and linear indicator of the net excitatory synaptic drive’ (Gorassini et al. 2002a), and because firing rate saturation can be a prevalent phenomenon, the utility of this method to characterize synaptic input requires further consideration.
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Rapid deactivation of plateau potentials
It is also possible in the present experiments that plateau potentials could have been instigated during the rising portion of the triangular contractions but actively extinguished during the falling phase. Indeed, a characteristic feature of plateau potentials is that they can be readily interrupted by brief injection of hyperpolarizing current or by synaptic inhibition (Hounsgaard et al. 1988; Kuo et al. 2003). Furthermore, voluntary muscle relaxation associated with the falling phase of triangular contractions might occur not only because of a progressive withdrawal of descending excitatory drive, but also because of concomitant engagement of descending pathways that inhibit motor neurones (Jankowska et al. 1976). Such synaptic inhibition might curtail plateau potentials initiated during the rising phase thereby eliminating evidence of plateau potentials during the falling phase. This is a possibility that cannot be discounted by the present experiments.
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Physiological conditions for plateau potentials
Ultimately, there is little doubt that the machinery for monoamine- and other neuromodulator-mediated persistent inward currents is a prominent feature of mammalian spinal neurones (Alvarez et al. 1998; Rekling et al. 2000; Hochman et al. 2001; Heckman et al. 2003) and that plateau potentials and ‘warm up’ effects can occur as evidenced by isolated studies. A more pertinent issue, however, relates to the physiological conditions under which these phenomena are expressed. In the present study, we found little evidence of a plateau potential meditated ‘warm up’ of motor units controlling either a hand or a postural muscle during weak isometric contractions based on previously proposed criteria. It is possible, as we have suggested above, that these criteria may not always be suitable for determining the activation of a plateau potential. On the other hand, it is also possible that for most types of ‘normal’ motor behaviours, motor neurones may operate in a milieu consisting of relatively low concentrations of monoamines. Microdialysis of monoamine concentrations in the ventral horn of the lumbar spinal cord of decerbrate cats (Lai et al. 2001) yield quite modest levels of serotonin (1–10 pM, Y.-Y. Lai, personal communication), several orders of magnitude less than that typically used to elicit plateau potentials in motor neurones during in vitro studies (e.g. 10–100 mM, Bennett et al. 2001; Perrier & Tresch, 2005). Furthermore, the concentration of extracellular serotonin in the ventral horn of freely behaving rats appears to decrease during exercise (treadmill running) compared to that measured at rest (Gerin & Privat, 1998).
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Perhaps then, it is only under ‘fight or flight’ conditions that there is sufficient monoamine input to the spinal cord to activate plateau potentials and thereby augment motor unit activity in situations of high stress or arousal (Heckman et al. 2003). It seems premature therefore to conclude that the monoaminergic-mediated persistent inward current associated with plateau potentials ‘provides the majority of current to drive normal recruitment and rate modulation’ (Heckman et al. 2005). The question of the physiological role of plateau potentials must remain open until methods are developed that allow monoamine concentration in the spinal cord to be readily monitored and plateau potentials to be unequivocally identified in awake behaving animals.
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