Does central fatigue exist under low-frequency stimulation of a low fatigue-resistant muscle?

Eur J Appl Physiol (2010) 110:815–823 DOI 10.1007/s00421-010-1565-9

ORIGINAL ARTICLE

Does central fatigue exist under low-frequency stimulation of a low fatigue-resistant muscle? Maria Papaiordanidou • David Guiraud Alain Varray

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Accepted: 24 June 2010 / Published online: 4 July 2010 Ó Springer-Verlag 2010

Abstract The aim of the present study was to determine whether central fatigue occurs when fatigue is electrically induced in the abductor pollicis brevis muscle. Three series of 17 trains (30 Hz, 450 ls, 4 s on/6 s off, at the maximal tolerated intensity) were used to fatigue the muscle. Neuromuscular tests consisting of electrically evoked and voluntary contractions were performed before and after every 17-train series. Both the force induced by the stimulation trains and maximal voluntary force generation capacity significantly decreased throughout the protocol (-27 and -20%, respectively, at the end of the protocol, P \ 0.001). These decreases were accompanied by failure in muscle excitability (P \ 0.01), as assessed by the muscle compound action potential (M-wave or Mmax), leading to significant impairment in the muscle contractile properties (P \ 0.05), as assessed by the muscle mechanical response (Pt). Central fatigue indices (level of activation, RMS/ Mmax and H reflex) were not significantly changed at any point in the protocol. This gives evidence of preserved motor command reaching the motor neurons and preserved spinal excitability. The results indicate that this low-frequency stimulation protocol entails purely peripheral fatigue development when applied to a low fatigue-resistant muscle.

Communicated by Alain Martin. M. Papaiordanidou (&)  A. Varray Motor Efficiency and Deficiency Laboratory/Movement to Health, Faculty of Sports Sciences, University Montpellier 1, 700 Avenue du Pic Saint Loup, 34090 Montpellier, France e-mail: [email protected] D. Guiraud LIRMM, DEMAR Team, INRIA, CNRS, University Montpellier 2, Montpellier, France

Keywords Muscle excitability  H reflex  Peripheral fatigue  Muscle afferents

Introduction Neuromuscular fatigue can be attributed to the physiological changes occurring at different sites, along the pathway of muscle activity, which have been traditionally classified as central or peripheral fatigue components. Central fatigue involves processes taking place before the neuromuscular junction (Gandevia 2001), while peripheral fatigue comprises those occurring distally to the neuromuscular junction (Allen et al. 2008). The dichotomy may appear confusing since there is no clear boundary between the nervous system and muscle, and the interactions between the various structures are complicated (Bary and Enoka 2008). Nevertheless, studies on human muscle fatigue have often used this distinction. Since the early work of Merton (1954) on muscle fatigue, various studies have examined the nature of fatigue induced by different types of exercise, including voluntary exercise like long-distance running (Millet et al. 2002; Racinais et al. 2007) and cycling (Lepers et al. 2002) and sustained or repeated voluntary contractions (Duchateau et al. 2002; Gandevia et al. 1998). These studies have shown that the nature of fatigue development is highly dependent on the task being performed, and that impairment in muscle capability to generate force is caused by failure of the mechanisms (one or more) that are being stressed during the task. Interest has also focused on electrically induced fatigue, under both high-frequency (Boerio et al. 2005) and low-frequency stimulation (Papaiordanidou et al. 2010). The results have demonstrated that, following electrical stimulation (ES), the impairment in muscle capacity to generate force during

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voluntary contractions is due to diminished neural drive to the muscle, independently of the stimulation frequency. Since failure of the central nervous system (CNS) to optimally drive the muscle can result from changes occurring at or above the spinal level, and given that spinal excitability was preserved in the aforementioned studies, it can be concluded that mainly supraspinal structures were implicated in the neuromuscular fatigue developed under ES. The results showing evidence of supraspinal fatigue development imply that central structures are involved in electrically induced fatigue, further reinforcing the literature on the non-purely peripheral character of ES (Gondin et al. 2005; Smith et al. 2003). Supraspinal fatigue, a component of central fatigue, can be attributed to suboptimal output from the motor cortex (Gandevia 2001), which has several possible causes. Increased afferent feedback from groups III and IV muscle afferents is a possible mechanism of this dysfacilitation. The input of these mechano- and metabo-sensitive afferents can act at the level of motor neurons or higher in the motor pathway, at supraspinal centers, and can modulate voluntary activation during fatiguing contractions (Gandevia et al. 1998; Taylor et al. 2006). Their central actions are poorly understood but appear to depend on the muscle group performing the task. Martin et al. (2006) gave evidence of a differential effect of their activation on the motor neuron pools of the elbow flexor and extensor muscles. Indeed, their increased activation had a facilitatory effect on the flexor but not the extensor muscles. In addition to these results, the study of Bigland-Ritchie et al. (1986) demonstrated that muscle function (flexor or extensor muscles) is not the only parameter influencing the appearance of central fatigue. In their study, central fatigue was apparent after fatiguing voluntary contractions in the soleus but not in the quadriceps muscle. Time to task failure for the soleus was *35 min, while for the quadriceps this time was much shorter, *4.5 min. The higher fatigue resistance observed for the soleus muscle than for the low fatigue-resistant quadriceps might be another variable that determines the susceptibility to central fatigue. Peripheral fatigue in muscles presenting great fatigability may occur earlier than in fatigue-resistant muscles, thus leaving no time for central fatigue to develop. These results indicate a relationship between the physiological mechanisms involved during the task and the nature of the studied muscle (high or low fatigue resistant), at least under voluntary contractions. We sought to determine whether the hypothesis that central fatigue development during voluntary fatiguing contractions depends on the muscle group being studied would be verified under electrically induced fatigue. We took into consideration the results of a previous study, which showed that intermittent low-frequency stimulation

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of the triceps surae provoked early central command failure without any impairment at the spinal or peripheral level (Papaiordanidou et al. 2010), and examined the physiological alterations, both qualitative and temporal, obtained when the same ES protocol was applied to a low fatigueresistant muscle. The abductor pollicis brevis (APB) muscle was chosen because it is known to be highly fatigable (Barandun et al. 2009). Independently of its reported fiber typology (60% of type I fibers; Johnson et al. 1973), the APB is a small, weak muscle with low resistance to fatigue (time to exhaustion at 50% of maximal force *3 min; Duchateau et al. 2002). The aim of the present study was to determine whether central fatigue occurs when a low-frequency ES is applied to the APB. Stimulation frequencies\30 Hz are commonly used in the clinical context to minimize the rapid onset of fatigue (Scott et al. 2005). We particularly focused on the kinetics of the fatigue components implicated by this stimulation protocol, which is more suitable to rehabilitation programs.

Materials and methods Subjects Thirteen healthy subjects [2 females and 11 males, mean age 28.5 (5.03) years] participated in the study. They were all physically active, with no history of wrist injury or recent operation of the upper limb. After being informed about the objectives and the eventual risks of participation in the study, all gave written consent. They were asked to maintain their usual daily activity throughout the experimentation period. The study was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the local Ethics Committee. Experimental design Subjects participated in two different sessions separated by 2 days. After an initial session of familiarization with the experimental procedure and the apparatus, an experimental session took place. During their first visit, they became accustomed to median nerve electrical stimulation, as well as to performing maximal voluntary contraction (MVC) of the APB. A recruitment curve was drawn in order to precisely identify the intensity at which the maximal M-wave and H reflex were obtained (see electrically evoked contractions). Maximal tolerated intensity for the ES protocol was also determined during this first visit. The experimental session began with a standard warmup consisting of ten light, submaximal isometric contractions of the APB, and it continued with the neuromuscular

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tests taking place every 17 stimulation trains [before (pre), during (post17 and post34) and immediately after the ES fatiguing protocol (post51)]. The neuromuscular tests duration was 90–120 s. Data collection Mechanical recording Abduction force of the right APB muscle was recorded with a custom-made calibrated rigid ergometer (Fig. 1), interfaced with an acquisition system (Biopac MP100, Biopac Systems Inc., Santa Barbara, CA, USA). Subjects were comfortably seated on a chair and had their right upper limb positioned on a horizontal board in a semi-supine position. The fingers and the forearm were securely attached to the ergometer with straps in order to minimize the contribution of adjacent muscles. Only the thumb was free to move and have contact with the recording part of the ergometer. Subjects were asked to push with the middle of the thumb against the strain gauge transducer (Captels, St-Mathieu de Treviers, France), which was aligned with the perpendicular axis of the produced force. EMG recording The surface EMG signals from the right APB and the extensor pollicis longus (EPL) muscles were recorded using bipolar, silver chloride, square surface electrodes with a 9-mm diameter (Swaromed, NesslerMedizintechnik, Austria). After verification of an appropriate M-wave acquisition (single response and highest amplitude), ensuring that the response was registered from a single muscle, electrodes were placed over the muscle

Fig. 1 Illustration of the experimental set-up. Neurostimulation was applied to the median nerve, while myostimulation was applied to the abductor pollicis brevis muscle (APB). EMG activity was recorded from the APB through the myostimulation electrodes and from the extensor pollicis longus (EPL). The ground electrode was placed in the wrist, between the neural stimulating electrodes and the EMG recording electrodes. Force was recorded by the force transducer, which was in contact with the middle of the thumb

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belly, with an interelectrode distance of 30 mm. The reference electrode was attached on the right wrist (between the stimulating and recording electrodes). Low impedance between acquisition electrodes was controlled (\5 kX) and obtained by abrading and cleaning the skin. The EMG signal was amplified (gain = 500) and recorded at a sampling frequency of 4,096 Hz (Biopac MP100, Biopac Systems Inc., Santa Barbara, CA, USA). Neuromuscular tests The neuromuscular tests consisted of electrically evoked contractions and MVC. Electrically evoked contractions The median nerve was stimulated by means of a high-voltage, constant-current stimulator (DS7AH, Digitimer Ltd., Hertfordshire, UK), delivering rectangular, monophasic pulses of 500-ls duration. The cathode and the anode (silver chloride surface electrodes, Swaromed, NesslerMedizintechnik, Austria) were placed one near the other over the pathway of the median nerve in the forearm, 8 cm from the EMG electrodes. The current intensity was progressively increased (10-mA increments, every 5 s) in order to identify the individual stimulation intensity at which no further increase in the amplitude of the compound muscle potential (M-wave) was observed. The stimulation intensity was then increased by 10% (supramaximal stimulation) to ensure synchronous recruitment of all muscle fibers. This supramaximal intensity (ISM) was used for the entire experimental session. Afterward, subjects were asked to perform a voluntary contraction at 10% of their MVC, during which weak single stimuli (every 10 s) eliciting the H reflex were delivered. Visual feedback of the generated force was provided, helping the subjects to perfectly match their force at 10% of their MVC. Intensity was increased by 2-mA increments, until the maximum H reflex was obtained (IHmax). When ISM and IHmax were determined, three single stimuli at ISM separated by 5-s intervals were delivered, and the Mmax and associated mechanical response were recorded at rest. Furthermore, three single stimuli at IHmax separated by 10-s intervals were delivered during the weak voluntary contraction in order to obtain the maximum H reflex. Maximal voluntary contractions Before the fatiguing protocol, all subjects performed three MVCs of the APB, interspaced by 1 min. During the protocol, they performed two MVCs, interspaced by 30 s. They were asked to maintain a maximal force plateau for 4 s. According to the twitch interpolation technique (Merton 1954), a twitch at ISM was delivered when the plateau was reached (superimposed twitch), as well as 2 s after relaxation (control twitch). All subjects were verbally encouraged to perform

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maximally, and the best trial was used for subsequent analysis.

LOAð%Þ

ES fatiguing protocol

Electrophysiological response The EMG activity of the APB was quantified by the root mean square (RMS) value of the filtered signal (10–500 Hz) at a 500-ms interval corresponding to the maximal force. In order to reduce the influence of peripheral factors (Lepers et al. 2002), the RMS value was subsequently normalized to Mmax (RMS/Mmax).

The fatiguing exercise was composed of three bouts of 17 stimulation trains. The APB was stimulated through the EMG recording electrodes. A portable stimulator was used (CefarPhysio 4, Cefar Medical AB, Lund, Sweden) to deliver constant-current, rectangular, symmetric biphasic pulses. Train characteristics were the following: frequency 30 Hz, pulse duration 450 ls, duty cycle 40% (4 s on, 6 s off), delivered at the maximal tolerated intensity. For the subjects participating in the study, this intensity varied from 11 to 40 mA [16.5 (8.46) mA]. Data analysis

¼ ½1  ðsuperimposed twitch=control twitchÞ  100:

ES fatiguing protocol The mechanical response of the APB was studied during the ES protocol. The force evoked by the stimulation trains was recorded and averaged for the first five and last five trains of each stimulation bout in order to obtain muscle response to the trains.

Twitches and evoked potentials Statistical analysis Mechanical response The following contractile parameters were calculated for the twitches eliciting Mmax (i.e., the average of the three responses evoked at rest): peak twitch (Pt), defined as the maximum value of force production to a twitch; contraction time (CT), the time needed from the beginning of the contraction to Pt; the maximum rate of force development (MRFD), the peak value of the derivative calculated in the ascending part of the force curve; the half-relaxation time (HRT), the time required for the force to decrease by 50% and the maximum rate of force relaxation (MRFR), the peak value of the derivative calculated in the descending part of the force curve. Electrophysiological response The EMG activity associated with the three twitches eliciting Mmax and Hmax was averaged for the analysis. The peak-to-peak amplitude and duration of Mmax were calculated. Its latency was also calculated as the time from the beginning of the stimulus artifact until the first peak of the M-wave. The amplitude of Hmax was also calculated and then normalized with respect to Mmax (i.e., Hmax/Mmax ratio) to avoid any impact of changes in membrane excitability. Moreover, the RMS value of the EMG signal during the 10% voluntary contraction was calculated on the 500-ms period preceding the stimuli eliciting the H reflex. Maximal voluntary contraction Mechanical response During MVC, the maximal force (mean value of 500 ms on the plateau) and the amplitudes of the superimposed and control twitches were studied. The level of voluntary activation (LOA) was calculated as follows (Allen et al. 1995):

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All variables recorded before, during and after the ES protocol were tested using a one-way (time) repeated measures ANOVA [before ES (pre), after 17 trains (post17), after 34 trains (post34) and after 51 trains (post51)]. In the case of a significant effect of time on the variables (P \ 0.05), the LSD Fisher post-hoc test was used. The normality of the distributions was verified with the Shapiro–Wilk test. Variables having a non-normal distribution were tested using a non-parametric Friedman ANOVA. Data are reported as means and standard deviation (SD), and the statistical significance was set at P \ 0.05. All statistical analyses were performed using Statistica software (StatSoft, Inc., version 7.1, Tulsa, OK, USA).

Results Force during the stimulation trains and the maximal voluntary contractions The force evoked by the trains of stimulation decreased during the ES protocol (Fr = 29.03, P \ 0.001). The decrease was significant at post34 and continued until the end of the fatiguing protocol (Fig. 2). From the value of 12.7 (6.7) N at the beginning of the protocol, the force decreased to 10 (4.5) N at post17, to 9.3 (4.6) at post34, and to 9.1 (4.6) at post51 (-27% compared with the initial value). The force evoked during MVC decreased throughout the ES protocol (F3 = 12.96, P \ 0.001). Figure 3 shows the percentage decline of force compared with the pre-value.

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Mmax (RMS/Mmax), there was no significant change at any point in the protocol compared with the pre-values (Fr = 0.41, P = 0.93). Table 1 shows the values of the electromyographic parameters throughout the testing procedure. LOA showed no significant change throughout the experiment (Fr = 1.71, P = 0.63; Table 1). Evoked potentials Maximum M-wave amplitude decreased during the experimental session (F3 = 5.71, P \ 0.01). After staying constant at post17, it started decreasing at post34 (-7%) and the decrease became significant at post51 (-11%, P \ 0.01), while its duration showed no significant modifications (F3 = 1.7, P = 0.18). M-wave latency also decreased during the ES protocol (Fr = 9.55, P \ 0.05). The decrease was significant from the first 17-train series (P \ 0.05) and continued for the entire protocol (P \ 0.05 for post34 and P \ 0.01 for post51). Details of the studied parameters are shown in Table 1. The H reflex amplitude was not significantly affected by the stimulation trains (Fr = 1.33, P = 0.72) even when H reflex was normalized to Mmax (Hmax/Mmax, Fr = 1.98, P = 0.57; Table 1). The RMS value preceding the stimulation evoking the H reflex remained constant throughout the experimental session (F3 = 0.66, P = 0.58).

Fig. 2 Force evoked by the trains of stimulation during the three series of the ES protocol. ***P \ 0.001 significantly different from pre-values

Fig. 3 Percentage of force decrease during maximal voluntary contraction after every 17-train series. ***P \ 0.001, significantly different from pre-values

Twitch contractile properties This decrease was 6, 15 and 20% at post17, post34 and post51, respectively.

The Pt decreased throughout the ES protocol (Fr = 7.43, P \ 0.05). The constant state at post17 was followed by a decrease of 5% at post34 that became significant only at post51 (-11%, P \ 0.05). CT and MRFD also showed a significant decrease at the end of the ES session (Fr = 10.86, P \ 0.05 and Fr = 10.11, P \ 0.05 respectively). Relaxation parameters (HRT and MRFR) showed no significant changes throughout the protocol. Details of the twitch contractile properties are presented in Table 2.

EMG activity and LOA during maximal voluntary contractions The raw RMS values of the APB muscle significantly declined throughout the protocol (F3 = 5.47, P \ 0.01). The decrease became significant at post34 (-10%, P \ 0.01) and post51 (-14%, P \ 0.01). When RMS was normalized to

Table 1 EMG activity, activation level, M-wave and H-reflex characteristics before the ES session and after each of the three ES bouts

pre

* P \ 0.05, ** P \ 0.01, significantly different from rest of the values

post34 0.51 (0.14)**

post51

RMS (mV)

0.58 (0.15)

0.56 (0.16)

RMS/Mmax

0.069 (0.013)

0.067 (0.015)

0.065 (0.011)

0.068 (0.018)

LOA (%)

79.31 (16.52)

79.68 (18.04)

79.57 (23.52)

77.08 (15.33)

8.5 (2.49)

8.56 (2.61)

8.09 (2.93)

7.64 (2.75)*

M-wave amplitude (mV)

Values are mean ± SEM

post17

M-wave duration (ms)

5.3 (1.6)

5.3 (1.5)

5.2 (1.5)

M-wave latency (ms) H reflex (mV)

6.53 (0.67) 0.8 (0.83)

6.44 (0.67)* 0.86 (0.73)

6.44 (0.6)* 0.9 (0.56)

0.49 (0.13)**

5.1 (1.4) 6.38 (0.63)** 0.78 (0.66)

Hmax/Mmax

0.08 (0.06)

0.09 (0.06)

0.1 (0.04)

0.096 (0.06)

RMSatH

0.14 (0.07)

0.13 (0.06)

0.13 (0.05)

0.13 (0.05)

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Table 2 Contractile properties before, during and after the ES protocol pre

post17

post34

post51

F

P

Pt (N)

2.94 (2.08)

2.94 (2.03)

2.66 (1.85)

2.48 (1.59)*

7.43

0.05

CT (s)

0.087 (0.037)

0.085 (0.039)

0.081 (0.034)

0.078 (0.036)*

10.86

0.05

105.53 (62.23)

106.24 (62.67)

96.29 (55.69)

87.96 (45.08)*

10.11

0.05

CT/Pt

0.041 (0.027)

0.038 (0.025)

0.038 (0.021)

0.039 (0.023)

0.33

0.79

HRT (s)

0.064 (0.011)

0.060 (0.016)

0.057 (0.018)

0.058 (0.019)

1.24

0.31

MRFR (N/s)

42.99 (23.96)

44.58 (23.33)

46.2 (27.23)

44.15 (22.86)

0.63

0.88

0.36 (0.26)

0.35 (0.21)

0.34 (0.18)

0.36 (0.24)

0.34

0.79

MRFD (N/s)

Pt/Mmax

Pt peak twitch, CT contraction time, MRFD maximum rate of force development, CT/Pt CT was normalized with respect to Pt to take into account the mechanical dependency of these two variables, HRT half-relaxation time, MRFR maximum rate of force relaxation, Pt/Mmax electromechanical index * P \ 0.05 significantly different from rest values

Discussion The results of the present study demonstrated that intermittent low-frequency electrical stimulation of the APB muscle provoked neuromuscular fatigue that could be attributed to peripheral fatigue development, without any implication of central factors. Neuromuscular fatigue was evident from the beginning of the ES protocol and was accompanied by failure in muscle excitability, as attested by the significant decreases in M-wave amplitude. The time course of central fatigue indices (no change in LOA, RMS/Mmax or H reflex) indicated that central drive and motor neuron excitability were preserved throughout the ES protocol. Muscle excitability was evaluated by eliciting the compound muscle action potential (M-wave) before, during and immediately after the ES fatiguing protocol, and the results indicated its impairment at the end of the protocol. Failure of action potential (AP) transmission at sites distal to the point of stimulation (nerve axon, neuromuscular junction, muscle membrane) can entail the decline of M-wave amplitude. At the neuromuscular junction, pre-synaptic (reduction in acetylcholine release) and post-synaptic (desensitization of acetylcholine receptors) processes are involved. However, under physiological conditions, the neuromuscular junction is known to remain unaffected (i.e., it provides 1:1 action potential transmission; Gandevia 2001). On the other hand, APs may fail to propagate either along each axonal bifurcation into the muscle (Grossman et al. 1979), thereby limiting the number of depolarized muscle fibers, or along the muscle membrane, due to decreased sarcolemmal excitability. Our results showing decreases in M-wave latency are consistent with preserved nerve conductivity compared to pre-values, leaving a failure of sarcolemmal excitability as the sole explanatory mechanism for the decrease in M-wave amplitude. Classically, failure of sarcolemmal excitability is attributed to changes in electrochemical gradients that

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prove impairment in the sodium–potassium pumps (Na?–K? pumps). This dysfunction causes high K? efflux from the myocytes to the extracellular spaces. The increased extracellular [K?] (and increased intracellular [Na?]) has been associated with a failure of excitation and a reduction in force (Allen et al. 2008). Failure of muscle excitability after high-frequency stimulation has been well documented in the literature (Badier et al. 1999; Darques et al. 2003; Zory et al. 2005). In the present study, low-frequency ES also provoked this alteration. This observation can be explained by the nature of the studied muscle. The APB muscle is a low fatigueresistant muscle (Barandun et al. 2009), and these muscles are known to be more sensitive to failure of muscle excitability (Pagala et al. 1984). Our results indicate that changes in sarcolemmal excitability are not only dependent on the stimulation frequency, as previously suggested (Badier et al. 1999; Zory et al. 2005), but are also influenced by other factors, like muscle fatigability. The force evoked by the stimulation trains during the ES protocol and the muscle capacity to generate voluntary force significantly declined throughout the ES protocol. These declines were accompanied by a significant decrease in the muscle mechanical response, but only after the third ES bout. The lack of early impairment of muscle contractile properties may be explained by potentiation, a phenomenon that can mask the effects of fatigue on muscle contractile properties by its opposite effects. While fatigue decreases the force evoked by a simple twitch, potentiation enhances the mechanical response. Since potentiation and fatigue arise from the beginning of exercise and appear following previous activation, these two phenomena can coexist (Rassier and MacIntosh 2000), making it difficult to distinguish their relative contributions to the simple twitch. The twitch should thus be considered as the result of forcepotentiating and force-diminishing effects. Kufel et al. (2002) observed that potentiated mechanical response is more sensitive to detect early fatigue than non-potentiated

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twitch, and as a consequence, the twitch evoked after the MVC is considered a better indicator of peripheral fatigue. However, the preservation of muscle contractile properties at post17 and post34 for the potentiated twitch is consistent with the transient preservation of parameters of the nonpotentiated mechanical response, further reinforcing the concept that fatigue and potentiation coexist. Muscle contractile properties are tightly controlled by intracellular calcium (Ca2?) movements, involving Ca2? release and re-pump from the sarcoplasmatic reticulum (SR) and contractile protein sensitivity to Ca2? (Allen and Westerblad 2001). It has been well documented in the literature that low-frequency ES entails intramuscular metabolic changes that influence muscle contractility (Darques et al. 2003). Increased myoplasmic inorganic phosphate (Pi) is a potential cause of contractile dysfunction by acting directly on the cross-bridge function or by reducing myofibrillar Ca2? sensitivity (Dahlstedt et al. 2001). Although Pi seems to be the most prominent cause of contractile impairment, there are other processes that can influence the Ca2? cycle, such as limited ATP availability or increased magnesium concentration, while the impact of elevated intracellular H? remains equivocal (Allen et al. 2008). Our results show altered Pt and MRFD and support the effect of these metabolites on the number of formed cross bridges and their attachment rate. However, the unchanged ratio Pt/Mmax (index of electromechanical coupling) indicates that most of the impairment was due to neuromuscular transmission failure, which consequently led to decreased contractile protein binding. Although muscle characteristics (excitability and consequently contractility) were impaired by the ES protocol, thus proving alterations occurring at the periphery, there was no central fatigue development at any point in the experimental session. Spinal excitability, as assessed by the H reflex during weak voluntary contraction and the Hmax/ Mmax ratio, remained unchanged. The decrease in force generating capacity could have entailed an increase in the neural drive arriving to motoneurons (to maintain the 10% MVC contraction) and hence would have affected the reflex gain. Similar RMS values, calculated during the weak sustained contraction, gave evidence of constant central input, further corroborating preserved spinal excitability. Raw RMS values significantly decreased during the protocol but, when normalized to Mmax, the time course of the ratio showed no changes over the session. A decrease in RMS values can be considered as an index of impaired neural drive to the muscle only in the case of no M-wave alterations (Lepers et al. 2002) because the EMG signal is inevitably influenced by processes occurring at the periphery (changes in impedance or neuromuscular propagation). When the M-wave amplitude is affected by the task, the decline in RMS is assumed to occur due to

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changes taking place at the muscle level. Given these findings and in addition to the results demonstrating no change in the LOA at any point in the protocol (b risk \ 10% throughout the protocol), we can assume that the central mechanisms implicated in force generating capacity were not affected by the ES session. Recent findings showed that the assessment of central fatigue by LOA or RMS/Mmax could present some limitations. First, LOA can overestimate central fatigue due to cellular contributions to the increment of the superimposed twitch under fatigue (Place et al. 2008). However, our results showed no change in LOA during the ES session, which is in agreement with no central fatigue overestimation bias. Second, RMS was described to present non-negligible intraday variations (Place et al. 2007). However, this bias can be reasonably excluded since the RMS values displayed a very regular decrease throughout the ES session. We assessed motor neuron excitability in the present study using the H reflex as a tool. An earlier study of electrically induced fatigue in the APB showed a failure in spinal excitability after a 30-Hz ES protocol (Duchateau and Hainaut 1993). Methodological considerations may explain the different results obtained in the present study. While in the aforementioned study the stimulation intensity used to fatigue the muscle was supramaximal, we delivered the ES protocol at the maximal tolerated intensity. Higher evoked force levels induce higher fatigue levels (BinderMacleod and Snyder-Mackler 1993) and can affect spinal excitability. Moreover, in the present study, fatigue was examined during and after a fixed duration of stimulation, while in the above-mentioned study the ES protocol continued until MVC force had decreased by 50%. These considerations, in addition to the fact that H reflexes were elicited during a sustained contraction corresponding to different percentages of the subject’s maximal force, can explain the discrepancies between results. Our observation that a fatiguing ES protocol carried out on the APB did not provoke any central alterations in the force generating pathway offers new insight into the electrically induced fatigue. Although a previous study (Papaiordanidou et al. 2010) demonstrated an early failure of central drive to the exercising muscle (triceps surae) under the same ES protocol, the present results on APB muscle show that peripheral fatigue components were at the origin of the subjects’ diminished capacity to generate voluntary force. Task dependency is a major principle in muscle fatigue research, the assumption being that the dominant cause of muscle fatigue is specific to the processes stressed during the fatiguing exercise (Enoka and Duchateau 2008). However, these results demonstrate that the nature of fatigue is not only task-dependent but also muscle-dependent. Indeed, under the same ES protocol, central fatigue was developed in the plantar flexors but not

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in the APB muscle. However, comparison between the two studies should be made with caution since central fatigue indices were not obtained with the same methodology. While LOA was assessed by doublet interpolation in the previous study, a simple twitch was used in the present study. A single stimulus superimposed on a MVC may not be sufficient to elicit enough extra force (Duchateau 2009), and this could have led to underestimation of LOA. However, the absence of modification in other indices of central fatigue (RMS/Mmax and H reflex) is in accordance with preserved central command during electrically induced fatigue on the APB muscle. The appearance of central fatigue for the ankle flexors but not for the APB under the same ES protocol can be explained by a differential effect of type III and IV muscle afferent activation. These afferents are sensitive to the muscle’s mechanical state and chemical milieu (Mense and Meyer 1985) and have projections to spinal (Garland and McComas 1990; Racinais et al. 2007) or supraspinal centers (Taylor et al. 2006). At the supraspinal level, they may inhibit cortical excitability (direct action at the motor cortex) or reorganize the circuits generating motor command (action above the level of motor cortical output), leading to progressive failure of voluntary activation. Concerning at least their spinal connections, Martin et al. (2006) observed a facilitatory effect of group III and IV muscle afferents on the elbow flexor but not extensor muscles during voluntary fatiguing contractions of these two muscle groups. These results suggest that the contribution of afferent feedback to the force decline is dependent on the muscle group. Thus, it could be hypothesized that differences in the projections of these afferents for the triceps surae and APB would explain the finding of supraspinal fatigue development for the former but not the latter muscle under the same ES protocol. Another explanation for the differences in central fatigue development between the two muscles could be the stimulation intensity used in the two studies. Indeed, the stimulation intensity was set to the pain threshold. As a consequence, the percentage of MVC evoked during stimulation was different in the studies (*40% for triceps surae vs. *20% for APB). It has been suggested that the higher intramuscular pressure in stronger muscles may lead to greater discharge of group III and IV muscle afferents (Hunter et al. 2006). As a consequence, central fatigue was clearly observed for the triceps surae only, despite greater fatigue obtained with the APB. In conclusion, this study presents evidence of peripheral fatigue development (failure in muscle excitability and consequently contractility) during low-frequency electrical stimulation of the abductor pollicis brevis, whereas central motor command and spinal excitability were preserved throughout the protocol. The results demonstrate that the

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nature of the stimulated muscle is a key factor in determining not only the extent of the fatigue, as proposed in the literature, but also the nature of the fatigue. The evidence that the nature of the muscle implies different central contribution to neuromuscular fatigue induced by lowfrequency stimulation may help clinicians to optimize stimulation strategies according to the muscle being studied. Acknowledgments The study was supported by the French Higher Education and Research Ministry. The authors would like to thank J.-P. Micallef for his help on the ergometer design. All experiments presented in the present study comply with the French laws for human experimentation. Conflict of interest statement no conflict of interest.

The authors declare that they have

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