MAGNETIC STIMULATION FOR FATIGUE

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Magnetic stimulation has been used extensively as a substitute for electrical stimulation in research and clinical evaluation of fatigue. The use of magnetic stimulation has been employed to stimulate peripheral nerves, the cervicomedullary junction and the motor cortex (by TMS).

PERIPHERAL MAGNETIC STIMULATION

Peripheral magnetic stimulation has been used in fatigue evaluation in both healthy and clinical populations. To date only a small number of studies have employed peripheral magnetic stimulation, with most investigations continuing to opt for electrical stimulation. A limiting factor in the use of peripheral magnetic stimulation is the distance between the targeted nerve and the coil. In individuals with a substantial layer of adipose tissue over the stimulation site, it may be impossible to achieve stimulus intensity supramaximality (Tomazin et al., 2011). When supramaximality is achieved, electrically- and magnetically-evoked single- and paired-pulse responses are comparable as demonstrated before and after 30 min of downhill running (Verges et al., 2009) (Figure 9). Several lower-limb studies have evaluated CAR in the quadriceps femoris with a magnetic pulse train delivered at maximal force (Kremenic et al., 2009; Glace et al., 2013) before and after cycling bouts. A restraint to the use of magnetic stimulation to evaluate CAR is that there are limits to stimulus frequency and intensity and their interaction, thus making the use of supramaximal-intensity stimulus trains problematic. Specifically, these studies state that they employed a pulse train at 40 Hz at an intensity of 100% maximal stimulator output. This protocol also required 8 booster units, so while theoretically possible, it is not practical for most laboratories or hospitals. Most lower-limb studies employing magnetic stimulation have evaluated VA by ITT.

These include

Figure 9. Peak evoked forces elicited in the relaxed muscle by electrical neural stimulation (ENS), magnetic neural stimulation (MNS) and electrical muscle stimulation (EMS) before (Pre), immediately after (Post), and 30 min after (Post30) exercise. All values are means ± standard deviations and presented as a percentage of Pre values. Panel A) Potentiated twitch amplitude (single pulse) and Panel B) potentiated doublet amplitude (paired pulse at 100 Hz). Adapted from Verges et al. (2009).
whole-body exercise protocols such as before and after a treadmill running marathon (Ross et al., 2007), before, during and after an intermittent cycling protocol (Decorte et al., 2012) and before and after a 6-min walk test in chronic obstructive pulmonary disease patients (Mador et al., 2001). Peripheral magnetic stimulation has also been used to investigate the effects of fatigue before, during and after isometric contraction protocols in both healthy (Bachasson et al., 2013b; Decorte et al., 2013) and clinical populations (Bachasson et al., 2013a; Bachasson et al., 2013c).

CERVICOMEDULLARY JUNCTION MAGNETIC STIMULATION

Cervicomedullary junction stimulation at the level of the foramen magnum and mastoids is employed to stimulate the corticospinal axons at the point closest to the brain that is not influenced by cortical excitability. Usually conducted by electrical stimulation, this painful method (McNeil et al., 2013) evokes single volleys in descending axons of upper motoneurons and elicits cervicomedullary-evoked potentials (CMEPs) in the muscle (Berardelli et al., 1991). Although it is recognised that ascending pathways and descending pathways in addition to the corticospinal tract will be triggered by a stimulus at the cervicomedullary junction, existing research suggests that these will have little if any influence on the production of CMEPs (Berardelli et al., 1991; Gandevia et al., 1999). The cervicomedullary junction can also be stimulated magnetically by placing the coil approximately over the inion (Taylor, 2006) although this is relatively rare since the distance from the spinal cord to the coil is large (~7-8 cm) causing the induced magnetic current to be sub-optimal at this depth. This likely explains why in fatigue studies employing cervicomedullary junction stimulation to elicit CMEPs, electrical stimulation of the cervicomedullary junction has usually (e.g. (Gandevia et al., 1999; Butler et al., 2003; McNeil et al., 2009; McNeil et al., 2011a; McNeil et al., 2011b; Sidhu et al., 2012a)) but not always (Levenez et al., 2008; Hoffman et al., 2009; Giesebrecht et al., 2011) been employed.

TRANSCRANIAL MAGNETIC STIMULATION

Transcranial magnetic stimulation is a non-invasive, safe and relatively painless technique to investigate the motor cortex. Unlike with peripheral stimulation, there are important differences between TMS and transcranial electrical stimulation. Transcranial electrical stimulation directly excites pyramidal tract axons at either the initial portion of the neuron or at proximal internodes within the subcortical white matter, eliciting descending D-waves. Conversely, TMS trans-synaptically excites the pyramidal neurons although direct excitation of pyramidal tract axons is believed to occur to various degrees depending on a variety of factors such as stimulus intensity (Houlden et al., 1999; Terao et al., 2000), coil orientation (Sakai et al., 1997; Terao et al., 2000) and muscle investigated (Day et al., 1989; Awiszus & Feistner, 1994; Houlden et al., 1999). The response to TMS is predominantly that of descending I-waves. D-waves indicate the degree of direct pyramidal tract stimulation. I- waves may also appear at short intervals and this is believed to represent repeated firing of pyramidal tract neurons after a cortical stimulus.
Transcranial magnetic stimulation can elicit both excitatory and inhibitory responses that present in EMG. These include both the MEP and cortical silent period (CSP) elicited by single-pulse TMS. MEPs are the recorded electrical responses in muscle elicited by TMS (Figure 8) and are a direct result of the descending D and I waves. Due to the possibility for TMS to cause multiple discharges of a single motoneuron, MEP amplitude/area can exceed that of Mmax. Changes in MEP amplitude/area are indicative of changes in cortical excitability (i.e. efficiency in motor command generation). Conversely, the CSP is the TMS-induced period of EMG near-silence after the MEP (Figure 10) and in the evaluation of fatigue is generally measured as the duration from TMS delivery to the resumption of continuous voluntary EMG (Taylor et al., 2000). Changes to CSP duration are proposed to be indicative of changes in intracortical inhibition. Additionally, paired TMS pulses can be used to assess changes in cortical facilitation (e.g. intracortical facilitation, ICF) and inhibition (e.g. short- (SICI) and long- (LICI) interval intracortical inhibition) (see sections below).
Figure 10. The cortical silent period (CSP). CSP is the duration from the delivery of TMS to the resumption of continuous voluntary EMG. Adapted from Taylor et al. (2000).
Initial investigations with TMS delivered single and then paired pulses while the muscle was in the relaxed state. Unlike peripheral nerve stimulation which stimulates the lower motoneurons that are unaffected or only marginally affected by voluntary contraction intensity (Todd et al., 2003; Lee & Carroll, 2005), TMS-induced motoneuronal output is greatly affected by the rapid increase in corticospinal excitability from rest to weak and moderate voluntary muscular contractions (Ugawa et al., 1995). Therefore, the investigation of central parameters (e.g. MEP, CSP, SICI, ICF, LICI) measured in contracting muscle before, during and after an exercise intervention permits greater understanding of the origins of corticospinal changes with fatigue than SIT alone. In isolation, TMS can only identify corticospinal changes. In conjunction with cervicomedullary junction stimulation, TMS can be used to partition responses and changes into cortical/supraspinal and spinal components.

Methodological issues

A major difficulty in interpreting the results of different protocols employing TMS is that there are many technical and methodological differences. For example, different stimulators cannot be compared due to differences in stimulator properties. Kammer et al. (2001) showed a difference in RMT between two stimulator systems and also between monophasic and biphasic waveforms. Similarly, the differential induced magnetic fields created by different coil types (i.e. circular, figure-of-eight, double-cone) and different winding diameters may lead to stimulation of different brain structures at the same coil position and stimulus intensity. It is unknown whether differences in equipment are capable of producing conflicting or contradictory results in the evaluation of fatigue. Fortunately, despite numerous companies manufacturing magnetic stimulators, most laboratories employing TMS to evaluate fatigue use Magstim stimulators, theoretically making comparison of stimulus intensities more feasible. It is also possible to employ two stimulators to deliver single TMS pulses at greater than 100% maximal stimulator output (The Magstim Co. Ltd., 2013). Furthermore, stimulus intensity is always presented as a percentage of maximal stimulator output. Without the use of standardized units, knowledge of the relationship between the percentage of maximal stimulator output and the resulting induced magnetic field or whether all stimulators of the same model induce identical magnetic fields under identical conditions (i.e. same stimulator intensity and same coil), comparison between studies remains difficult.
Determination of optimal coil position has been largely mysterious. Most studies have indicated that the optimal coil position was where the largest MEP was elicited. Information concerning such details as the stimulus intensity to determine the position, whether this was conducted with the muscle relaxed or during voluntary contractions and the number of responses considered for each site is generally lacking. Furthermore, the use of posterior-anterior current in the brain (Davey et al., 1994; Rossini et al., 1994; Kammer et al., 2001; Groppa et al., 2012) is standard in many TMS studies, including those investigating fatigue of the lower limbs (Goodall et al., 2009; Sidhu et al., 2009b; Goodall et al., 2010; Goodall et al., 2012; Iguchi & Shields, 2012; Sidhu et al., 2012a; Sidhu et al., 2013b). This is despite some studies suggesting that other coil orientations stimulate different muscles better than others (Mills et al., 1992; Werhahn et al., 1994), including differences between upper- and lower-limb muscles (Rosler et al., 1989). In all cases, the rationale for utilization of a certain coil orientation is because studies have shown it to identify the lowest RMT (Davey et al., 1994; Balslev et al., 2007). The only apparent rationale for assessing the efficacy of coil orientation to minimize the intensity at RMT and not on the size of the elicited responses (e.g. MEP) is that this method permits the selection of lower TMS stimulus intensities since many studies have used RMT to determine stimulus intensity.
While most studies have used RMT as a basis to determine TMS intensity, the evaluation of fatigue inherently requires muscular contraction. Recently, other methods have been employed to determine TMS intensity and these include active motor threshold (i.e. the minimum stimulus intensity to elicit a MEP in at least half of responses when the muscle is contracted weakly, e.g. 3-10% MVC; AMT) (e.g. (Kalmar & Cafarelli, 2006; Iguchi & Shields, 2012)), stimulus-response curves (Rupp et al., 2012) and a stimulus intensity to evoke MEP responses of a certain size in the target muscle during voluntary contraction (e.g. (Sidhu et al., 2009b; Klass et al., 2012)). The advantages and disadvantages of these methods have not yet been elucidated. Table 1 details methodological aspects of TMS investigations in the lower limbs that have selected a specific TMS intensity for investigative purposes. These include the coil and stimulator used, the methods of determining both coil position and stimulator intensity and the stimulator intensity selected.
The best method of determining TMS intensity remains to be determined. It is unknown whether the different methods employed to determine TMS intensity result in selection of the same intensity. Furthermore, it is unknown whether selection of TMS stimulus intensity should always be conducted in the same manner. Current recommendations principally address evaluations for clinical purposes (Groppa et al., 2012) and it remains to be determined if these can be applied to the evaluation of fatigue in a healthy population. It also remains to be investigated if the manner of approaching a target force influences elicited responses, particularly because of the importance of contraction intensity on corticospinal excitability.

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Upper limbs

TMS investigations began with muscles of the hand and arms. In the motor cortex, these muscles are much better represented than the muscles of the lower limbs. As previously described, magnetic stimulation began with circular coils that lacked precision, thus rendering TMS only feasible in the upper limbs.

Cortical voluntary activation

As in isometric MVCs with peripheral neural stimulation, the SIT evoked by TMS can increase, indicating that supraspinal mechanisms contribute to the observed fatigue (Gandevia et al., 1996). While the presence of increased SIT indicates the presence of supraspinal fatigue, it does not eliminate the possibility of spinal contributions to central fatigue. The increased SIT only means that despite the increasing possibility for improved neural drive from the motor cortex, the brain is unable to provide it. Increased TMS-evoked SIT at maximal force has been observed in upper-limb muscle groups in both intermittent (Hunter et al., 2008) and continuous (Todd et al., 2005) fatiguing exercise protocols. During sustained submaximal contractions, there was a gradual development of supraspinal fatigue that was demonstrated by increasing SIT at the submaximal contraction intensity and confirmed during brief MVCs at regular intervals during low-intensity sustained elbow-flexor contractions of 5% (Smith et al., 2007) and 15% (Sogaard et al., 2006) MVC (Figure 11). Cortical voluntary activation (VAc) assessed by TMS is more complicated than ITT with peripheral nerve stimulation (Todd et al., 2003) since it is inappropriate to compare SIT elicited during MVCs to evoked responses in the relaxed muscle. The large increase in corticospinal excitability from rest to even weak voluntary muscular contractions (Ugawa et al., 1995) means that TMS-induced motoneuronal output at rest is not representative of that at maximal voluntary force. Therefore a potentiated twitch induced by TMS delivered in the relaxed muscle would be greatly underestimated, and thus underestimate the cortical drive to the muscle. Todd et al. (2003) proposed the extrapolation of the linear relationship between SIT and voluntary force between 50 and 100% MVC to estimate the amplitude of the resting twitch that would be produced by TMS under comparable conditions of corticospinal excitability. Originally applied in the elbow flexors (Todd et al., 2003), the validity and reliability of extrapolating the relationship between TMS-evoked SIT and voluntary forces at 50%, 75% and 100% MVC has also been confirmed in the wrist extensors (Lee et al., 2008).
Figure 11. The evolution of SIT during a 43-min sustained isometric contraction at 15% MVC and during recovery contractions at 15% MVC. The broken vertical line denotes the end of the 43-min sustained contraction. Adapted from Sogaard et al. (2006).
It is acknowledged that VAc can be quantified by this method in fresh and fatigued muscles although there are some methodological concerns in addition to those associated with peripheral assessment of VA (VAp). The regression of voluntary force and the SIT is almost always linear in the unfatigued state, allowing estimation of resting twitch amplitude, and therefore VAc (Todd et al., 2003; Hunter et al., 2006; Cahill et al., 2011). This relation may frequently be non-linear (r < 0.9) during or after a fatigue protocol (e.g. up to one-third of contraction sets in Hunter et al. (2006; 2008)), thus preventing the estimation of the resting twitch in some subjects (del Olmo et al., 2006; Hunter et al., 2006; Hunter et al., 2008). To obtain a valid linear extrapolation, it is essential that the stimuli activate most of the motoneurons, which is possible at high levels of voluntary force (i.e. > 50% MVC in biceps brachii and brachioradialis) as demonstrated by MEPs of maximal amplitude (Taylor et al., 1997; Todd et al., 2003). Indeed, TMS is less effective at activating motoneurons at lower contraction intensities because of reduced corticospinal excitability (Todd et al., 2003). This is demonstrated by a curvilinear relationship between SIT and voluntary force at contraction strengths below 50% MVC (del Olmo et al., 2006; Lee et al., 2008). It may also be impossible to obtain a SIT at high contraction intensities (>75% MVC) (del Olmo et al., 2006), a phenomenon also observed in ITT with peripheral nerve stimulation (discussed in (de Haan et al., 2009; Taylor, 2009)). Therefore, if a SIT can be evoked at near-maximal contraction intensities and if the SIT-voluntary force relationship (50-100% MVC) is linear (r  0.9), then it is appropriate to estimate resting twitch amplitude and calculate VAc.
During sustained maximal (Hunter et al., 2006; Szubski et al., 2007) and submaximal (Smith et al., 2007) isometric fatiguing contractions, VAc decreases, suggesting that supraspinal fatigue develops progressively. The evaluation of VAc with dynamic upper-body exercise has never been conducted; therefore it is unknown whether VAc changes with a similar time-course during dynamic exercise. As with the presence of increased SIT during sustained voluntary contractions, the decreased VAc observed in the aforementioned studies and indicating the presence of supraspinal fatigue does not eliminate the possibility of spinal contributions to central fatigue. Furthermore, the proportion of central fatigue corresponding to each level of the motor pathway cannot be completely elucidated without the combination TMS and cervicomedullary and spinal nerve root stimulation. Smith et al. (2007) attempted to quantify the amount of central fatigue originating solely at the supraspinal level. This was done by determining the post-intervention MVC if VAc had remained unchanged. The additional decrease in MVC was attributed to a decrease in VAc (i.e. supraspinal fatigue). After a 70-min 5% MVC sustained elbow flexion, they concluded that 66% of the decrease in MVC was due to supraspinal fatigue. It remains to be determined whether this is a valid method of quantifying supraspinal fatigue in isolation.

Table of contents :

LITERATURE REVIEW
CENTRAL FATIGUE AND CEREBRAL PERTURBATIONS
WITH EXERCISE
CENTRAL FATIGUE
TECHNIQUES OTHER THAN NEURAL STIMULATION TO INVESTIGATE
MECHANISMS OF CENTRAL FATIGUE
Electromyography
Near-infrared spectroscopy
Doppler ultrasound
Magnetic resonance imaging
Electroencephalography
NEUROMUSCULAR STIMULATION
ELECTRICAL STIMULATION
MAGNETIC STIMULATION
Coils
Circular coils
Figure-of-eight coils
Double-cone coils
Stimulator types
Monophasic
Biphasic
MAGNETIC STIMULATION FOR FATIGUE
PERIPHERAL MAGNETIC STIMULATION
CERVICOMEDULLARY JUNCTION MAGNETIC STIMULATION
TRANSCRANIAL MAGNETIC STIMULATION
Methodological issues
Upper limbs
Cortical voluntary activation
Motor-evoked potentials
Cortical silent period
Paired pulses
Lower limbs
Cortical voluntary activation
Motor-evoked potentials
Cortical silent period
Paired pulses
TRANSCRANIAL MAGNETIC STIMULATION HIGHLIGHTS
SLEEP DEPRIVATION
SLEEP DEPRIVATION HIGHLIGHTS
ULTRA-ENDURANCE EXERCISE
ULTRA-ENDURANCE EXERCISE HIGHLIGHTS
REVUE DE LA LITTERATURE
FATIGUE CENTRALE
STIMULATION MAGNETIQUE
STIMULATION MAGNETIQUE POUR LA FATIGUE
STIMULATION MAGNETIQUE TRANSCRANIENNE
Membres supérieurs
Membres inférieurs
PRIVATION DE SOMMEIL
EXERCICE D’ULTRA-ENDURANCE
INTRODUCTION TO STUDIES 1 AND 2
STUDY 1
ABSTRACT
RÉSUMÉ
INTRODUCTION
METHODS
RESULTS
DISCUSSION
STUDY 2
ABSTRACT
RÉSUMÉ
INTRODUCTION
METHODS
Subjects
Experimental design
Force and electromyographic recordings
Femoral nerve stimulation
Transcranial magnetic stimulation
Determination of coil position
Determination of stimulus intensity
Data analysis
Statistics
RESULTS
Selected stimulus intensity
Boltzmann sigmoidal curves
DISCUSSION
Comparison of methods
Resting motor threshold
Active motor threshold
Stimulus-response curves
Comparison of muscles
Conclusion
INTRODUCTION TO STUDIES 3 AND 4
STUDY 3
ABSTRACT
RÉSUMÉ
INTRODUCTION
METHODS
Subjects
Experimental design
Preliminary visit
Experimental conditions
Sleep, activity and condition control
Force and Electromyography
Femoral nerve stimulation
Transcranial magnetic stimulation
Neuromuscular testing
Cognitive task
Exercise protocol
Data analysis
Activity
Peripheral nerve stimulation
Transcranial magnetic stimulation
Cognitive task
Statistics
Exercise and neuromuscular responses
Cognitive task
RESULTS
Sleep patterns and sleepiness
Performance, RPE and HR during exercise
Neuromuscular responses
Maximal voluntary and evoked forces
M-waves
TMS stimulus intensity
Voluntary activation
Motor-evoked potentials (at optimal stimulus intensity)
Motor-evoked potentials (at sub-optimal stimulus intensity)
Cortical silent period
Cognitive task
Reaction time
Decision errors and omissions
DISCUSSION
Cycling performance
RPE and HR
Neuromuscular function
Cognitive performance, sleep deprivation and exercise
Limitations
Conclusion
STUDY 4
ABSTRACT
RÉSUMÉ
INTRODUCTION
METHODS
Subjects
Experimental design
PRELIMINARY SESSION
Neuromuscular testing protocol
Force and electromyographic recordings
Femoral nerve electrical stimulation
Transcranial magnetic stimulation
Data analysis
EMG and femoral nerve electrical stimulation
Transcranial magnetic stimulation
Statistics
RESULTS
Performance
Maximal voluntary torque and evoked responses
M-waves and RMS
Voluntary activation
Motor-evoked potentials
Cortical silent period
DISCUSSION
Maximal torque and PNS measures: comparison with the literature
Centrally- and peripherally-assessed voluntary activation
Motor-evoked potentials and cortical silent periods
Limitations
Conclusion
GENERAL DISCUSSION AND PERSPECTIVES
DISCUSSION
PERSPECTIVES
DISCUSSION GENERALE ET PERSPECTIVES
DISCUSSION
PERSPECTIVES
REFERENCES
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