Neuromuscular fatigue during exercise

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Neuromuscular fatigue during exercise: Methodological considerations, etiology and potential role in chronic fatigue La fatigue neuromusculaire au cours de l’exercice : considérations méthodologiques, étiologie et rôle potentiel dans la fatigue chronique Rosie Twomey , Saied Jalal Aboodarda , Renata Kruger , Susan Nicole Culos-Reed , John Temesi , Guillaume Y. Millet ∗ Human Performance Laboratory, Faculty of Kinesiology, University of Calgary, 2500, University Dr NW, T2N 1N4 Calgary, Alberta, Canada

KEYWORDS Cancer; Central; Multiple sclerosis; Peripheral; Transcranial magnetic stimulation

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Summary The term fatigue is used to describe a distressing and persistent symptom of physical and/or mental tiredness in certain clinical populations, with distinct but ultimately complex, multifactorial and heterogenous pathophysiology. Chronic fatigue impacts on quality of life, reduces the capacity to perform activities of daily living, and is typically measured using subjective self-report tools. Fatigue also refers to an acute reduction in the ability to produce maximal force or power due to exercise. The classical measurement of exercise-induced fatigue involves neuromuscular assessments before and after a fatiguing task. The limitations and alternatives to this approach are reviewed in this paper in relation to the lower limb and whole-body exercise, given the functional relevance to locomotion, rehabilitation and activities of daily living. It is suggested that under some circumstances, alterations in the central and/or peripheral mechanisms of fatigue during exercise may be related to the sensations of chronic fatigue. As such, the neurophysiological correlates of exercise-induced fatigue are briefly examined in two clinical examples where chronic fatigue is common: cancer survivors and people with multiple sclerosis. This review highlights the relationship between objective measures of fatigability with whole-body exercise and perceptions of fatigue as a priority for future research, given the importance of exercise in relieving symptoms of chronic fatigue and/or overall disease management. As chronic fatigue is likely to be specific to the individual and unlikely to be due to a simple biological or psychosocial explanation, tailored exercise programmes are a potential target for therapeutic intervention. © 2017 Elsevier Masson SAS. All rights reserved.

Corresponding author. E-mail address: [email protected] (G.Y. Millet).

http://dx.doi.org/10.1016/j.neucli.2017.03.002 0987-7053/© 2017 Elsevier Masson SAS. All rights reserved.

Please cite this article in press as: Twomey R, et al. Neuromuscular fatigue during exercise: Methodological considerations, etiology and potential role in chronic fatigue. Neurophysiologie Clinique/Clinical Neurophysiology (2017), http://dx.doi.org/10.1016/j.neucli.2017.03.002


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MOTS CLÉS Cancer ; Central ; Périphérique ; Sclérose en plaques ; Stimulation magnétique transcrânienne

Résumé Le terme fatigue est utilisé pour décrire un symptôme pénible et persistant de fatigue physique et/ou mentale dans certaines populations cliniques, avec une pathophysiologie distincte, mais finalement complexe, multifactorielle et hétérogène. La fatigue chronique a des répercussions sur la qualité de vie, réduit la capacité d’effectuer des activités de la vie quotidienne et est généralement mesurée à l’aide d’outils subjectifs d’auto-évaluation. La fatigue se réfère également à une réduction aiguë de la capacité à produire une force ou puissance maximale au cours de l’exercice. La mesure classique de la fatigue induite par l’exercice implique des évaluations neuromusculaires avant et après une tâche fatigante. Les limites et les solutions de rechange à cette approche sont revues dans cet article en rapport avec l’exercice du membre inférieur et corps-entier, étant donné la pertinence fonctionnelle de cela en ce qui concerne la locomotion, la réadaptation et les activités de la vie quotidienne. Nous suggérons que les altérations des mécanismes centraux et/ou périphériques de la fatigue au cours de l’exercice puissent être liées aux sensations de fatigue chronique. Ainsi, les corrélats neurophysiologiques de la fatigue induite par l’effort sont brièvement examinés dans deux exemples cliniques : les survivants du cancer et les personnes atteintes de sclérose en plaques. Cette étude met en évidence la relation entre les mesures objectives de fatigabilité liée à l’exercice corps-entier et les perceptions de fatigue comme une priorité de recherche pour le futur, étant donné l’importance de l’exercice pour soulager les symptômes de la fatigue chronique et/ou la gestion globale de la maladie. Comme la fatigue chronique est susceptible d’être spécifique à l’individu et qu’il est peu probable qu’elle est due à une simple explication biologique ou psychosociale, des programmes d’exercices adaptés représentent une stratégie potentielle de traitement. © 2017 Elsevier Masson SAS. Tous droits r´ eserv´ es.

Introduction The term fatigue is defined by the Oxford Dictionaries as ‘‘extreme tiredness resulting from mental or physical exertion or illness’’ and originates from the Latin fatigare—‘‘to weary, to tire out’’ [182]. In this context, the effects of fatigue have received attention in occupations where extreme tiredness can have serious consequences, such as in pilots [79], military personnel [205], fire-fighters [39] and surgeons [183]. In addition, the term fatigue is used to describe a non-specific but debilitating symptom in a range of chronic diseases and disorders such as cancer [129], multiple sclerosis [101], stroke [32] and depression [11]. The subjective nature and severity of fatigue in healthcare is assessed using psychometric tools such as self-report questionnaires and scales [48,207]. There is no all-inclusive definition of clinical fatigue but the distinction from other uses of the term is that the symptom is the result of an underlying pathophysiology or its associated treatment. The term fatigue is also used in relation to a decline in performance induced by exercise, where exercise is defined inclusively as muscle activity with the potential to disrupt homeostasis [209]. Understanding fatigue in the context of the limitations to exercise performance has been a major research agenda for exercise physiologists for over a century [78,133]. Lively debate continues to enrich the literature and has provoked consideration across the entire discipline of exercise science [9,19,112,144]. The relative merit of objective and subjective measures of fatigue is dependent on the theoretical framework of study. For example, in a clinical population where fatigue may be chronic and have a devastating impact on quality of life (QoL) and/or physical function, a multidimensional approach is clearly warranted. In contrast, investigation

of the mechanisms of fatigue following a specific exercise task may primarily rely on objective physiological measures [125]. It follows that generic use of the term fatigue without explicit definition or consideration of fatigue-related phenomena in different populations or contexts can be problematic. This highlights the inadequacy of the single term ‘‘fatigue’’ for concepts which are readily acknowledged by both exercise scientists and clinicians as being multifactorial, interactive and complex. A taxonomy was suggested for use in clinical research using two domains: perceptions of fatigue and performance fatigability [97] and it was recently proposed that this framework should be implemented as a foundation to unify research in human performance [50]. There is certainly value in adopting a cohesive nomenclature and the emphasis in this review is on describing fatigue according to the application and the techniques used to measure it. An early model of exercise-induced fatigue proposed that exercise is limited by muscle lactate accumulation secondary to an inadequate supply of oxygen due to a limited cardiac output [78]. In opposition to this model where exercise termination was considered the result of skeletal muscle anaerobiosis, the central governor/complex systems model proposes that exercise is regulated in an anticipatory manner, to ensure exercise terminates before catastrophic biological failure [102,142]. The latter model involves feed forward motor output to recruit an appropriate number of motor units (based on numerous physiological and psychological factors), continuous modification of pace via feedback from conscious sources and allows for the presence of an end-spurt in closed-loop tasks [143]. There are multiple models of fatigue [1,141] but a crucial divide is whether fatigue is studied with respect to a change in motor performance (for example, a decrease in the ability to



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Fatigue & Exercise produce force), or as a conscious perception of a sensation [147] with or without a change in motor performance. It has been proposed that fatigue includes both an increase in the perceived effort necessary to exert a desired force and an eventual inability to produce said force [51]. In contrast, some research groups consider fatigue to be an emotion rather than a physical event [143,179], derived and used by the brain to regulate exercise performance [201]. It is often difficult to extrapolate the findings from one approach to another since different experimental designs provide information about different processes. The approach taken to study exercise-induced fatigue also varies between research groups due to techniques used by diverse specialist fields, e.g. magnetic peripheral stimulation in respiratory medicine vs. electrical stimulation in neurology and sport sciences. In view of the recent suggestions in regards to clarity, the focus of this review is on both a decline in objective physiological measures over a discrete period of time and the subjective experience of fatigue (termed ‘‘performance fatigability’’ and ‘‘perceptions of fatigue’’, respectively [50,97]). A somewhat underexplored area for consideration is the relationship between mechanisms of exercise-induced fatigue and the chronic fatigue present in many clinical populations. As previously highlighted, establishing the relationship between these distinct and often independent concepts, is a priority for future research [97]. In particular, we will provide two examples of clinical populations (cancer survivors and people with multiple sclerosis, PwMS), where objective physiological measures related to a reduced fatigue resistance may be associated with increased perceptions of fatigue during exercise and/or activities of daily living. In other words, neurophysiological measures to determine central and peripheral factors during acute exercise may aid in the understanding of chronic fatigue. Where data are available, this review will primarily consider mechanisms of neuromuscular fatigue in the lower limbs during single-joint and whole-body exercise (mainly running and cycling), where whole-body exercise is considered to be bilateral, dynamic and that which involves large muscle groups. This is due to the functional relevance to locomotion, rehabilitation and activities of daily living in clinical populations. Within this review, exercise-induced fatigue is considered to be a deficit originating in the nervous and/or muscular system, in relation to the integration of mechanisms and regulatory functions at a number of biological levels. As such, a number of fascinating topics broadly related to fatigue or exercise performance fall outside of the scope of this review. In particular, the reader is directed to examples elsewhere in regards to the conscious perception of effort [145,177], mental fatigue [114], exercise-induced pain [117], overtraining [118], automonic nervous system changes [171] and deteriorated metabolic/mechanical cost of locomotion [65].

Part 1: acute fatigue as a reduction in maximal performance Historically, fatigue was defined as a failure to maintain the required force to maintain a task [47]. It is now well established that this definition is invalid: fatigue develops gradually during sustained physical activity, not solely at the

3 point of task failure [62]. A more accurate definition should reflect this and also distinguish fatigue from muscle damage or muscle weakness (which persists over longer time periods and can be independent from exercise [203]), in that it is reversible by rest [58]. A common definition is therefore any exercise-induced reduction in the ability of a muscle to generate force or power, reversible by rest [12,36]. An extension to this definition is ‘‘a circumstance where less than the anticipated contractile response is obtained’’ [109], which is sensitive to progressive changes in muscle contractile properties in that it incorporates a reduced force at low stimulation frequencies even though maximal force may be maintained.

Classical measurement of exercise-induced fatigue By the common definition (a reduced ability to generate force), one classical protocol used to quantify fatigue is to measure the decline in maximal voluntary force produced during brief isometric contractions from baseline to immediately after the fatiguing task [203]. A maximal voluntary contraction (MVC) is a brief, maximal-effort contraction performed with continuous feedback and encouragement [63]. As previously underlined [50], it should not be assumed that the perceptions of the sensations, which accompany a fatiguing task, are independent from the neuromuscular adjustments required to sustain the task. In fact, there is widespread agreement that disengagement from a task involves input to higher areas of the central nervous system (CNS) [8,89,143,147] and that the main regulatory responses to exercise defy simple or reductionist explanations [71,86]. The core of integrative fatigue paradigms is that the CNS is highly involved in the regulation of exercise performance [19]. Hence, the definition of fatigue is used to facilitate an approach to investigate sites in the neuromuscular system where deficits can occur, while acknowledging that impairment in voluntary force may interact with complex regulatory processes, which contribute to exercise termination. Typically, neuromuscular fatigue is assessed at volitional exhaustion or task failure. The decision to disengage from a task in this way is ultimately a behaviour, i.e. an internally coordinated response to internal and/or external stimuli [107]. It is important to appreciate the inadequacy of ascribing a behaviour to changes in lower-level neurophysiological properties; a broader perspective, which has recently been appraised [98]. Nevertheless, using stimulation techniques before and after a fatiguing task allows the evaluation of the points in the pathway, from the primary motor cortex to the muscle, which contribute to neuromuscular fatigue. In this sense, fatigue is categorised broadly as having peripheral and central components [51], both of which have long been acknowledged [133] and interrelated. The peripheral contribution to neuromuscular fatigue Peripheral fatigue is defined as a loss of maximal force due to processes occurring at, or distal to, the neuromuscular junction [17,62]. The outcome of these processes in the intact human muscle can be measured using supramaximal electrical or magnetic stimulation of its motor nerve (thus, bypassing the brain and spinal cord). For example,



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the femoral nerve can be stimulated to evoke a muscle twitch or a tetanus, which can be used for the evaluation of non-volitional quadriceps strength and fatigue [150]. This technique has been used after exercise in athletic and clinical populations for over three decades [37,104,111]. A decrease in the amplitude of the evoked response is used as a global measure of locomotor muscle fatigue and the technique is sensitive for detecting relatively small disturbances [111]. It is difficult to distinguish between different factors contributing to peripheral fatigue as changes may occur in parallel at a multitude of sites. The cellular mechanisms of skeletal muscle fatigue in isolated muscle have been reviewed elsewhere [6,58,110] and remain under investigation [25]. Data obtained under tightly controlled physiological conditions in vitro and in situ provide insight into the possible neural and biochemical processes. However, the gold standard for the study of fatigue is to examine the muscle in vivo [6]. There are a number of parameters that can be examined from the mechanical response to single stimulations and high-frequency doublets/tetani, which can be used to infer fatiguing mechanisms at the cross-bridge cycle (which include a direct inhibition of the function of contractile proteins and a reduced Ca2+ sensitivity caused by accumulating metabolites [41]). Lowfrequency fatigue (a relative loss of force at low stimulation frequencies) can also be assessed using a doublet or tetanus at 10—20 Hz normalised to the response at high frequency (> 50 Hz, typically 80—100 Hz). This type of fatigue is typically slow to recover and is associated with failure in excitation-contraction (E-C) coupling, i.e. depressed Ca2+ release [125]. Alterations in the electromyographical (EMG) response (the muscle compound action potential, M-wave) to peripheral nerve stimulation provide insight into the integrity of neuromuscular transmission/action potential propagation, although M-wave responses can be contaminated by other parameters such as change in temperature, sweat, etc.

The central contribution to neuromuscular fatigue Multiple fatiguing processes also originate proximal to the neuromuscular junction i.e. within the CNS. Central fatigue can be defined as a progressive reduction in the voluntary activation (VA) of muscle during exercise [62]. VA is conventionally measured using the interpolated twitch technique (ITT), where a supramaximal stimulation is delivered during a MVC [120]. Alternative methods more rarely used are the central activation ratio, where a tetanus is superimposed on a MVC [116], or by comparing a MVC with a high-frequency supramaximal tetanus [123]. During the ITT, if an increment in force above that being produced volitionally is present i.e. a superimposed twitch (SIT), VA is considered incomplete. The presence of the SIT indicates that some motor units were not recruited or were not firing fast enough to produce fused contractions at the moment of stimulation [188]. To quantify VA, the amplitude of the SIT is normalised to the amplitude of the twitch evoked by the same stimulus in the potentiated relaxed muscle (i.e. after a brief MVC). The ITT has been subject to methodological debate [34,59,64,138], but is generally considered to be a useful tool [187]. In the non-fatigued knee extensors, VA is high but incomplete, with typical values of 90—95% [149,175]. However, the

traditional ITT method is limited in that the impairment in VA can occur at any site proximal to the motor axons where the stimulation is delivered and no further information about what levels of the nervous system are contributing to the impairment can be obtained. In 1980, Merton and Morton were the first to produce a movement of limb muscles using electrical stimulation of the contralateral motor cortex through the intact human scalp using a large single shock [121]. In 1985, Barker et al. discovered that a magnetic field also was capable of activating the motor cortex non-invasively [13]. Transcranial magnetic stimulation (TMS) was quickly accepted by the major research group stimulating the cortex through the scalp in humans [162] and has since achieved widespread impact and success [212]. TMS involves a rapidly changing magnetic field delivered with a coil held over the scalp, which through the principle of electromagnetic induction, induces a weak electrical current that excites underlying neural tissue [73]. The cortical representation of the lower limbs can be stimulated with a double-cone coil and in comparison to the discomfort of electrical stimulation, is relatively painless. TMS can be used to further localise the site of central fatigue as traditionally measured using the ITT. Despite maximal volitional effort, TMS over the motor cortex can also elicit extra force production [63]. A suboptimal cortical VA (VATMS ) indicates that the output from the motor cortex is not driving the muscle maximally at the time of stimulation [190]. When a SIT is evoked cortically during a MVC, this implies that extra output from the motor cortex is available, as TMS is able to evoke extra force that cannot be produced voluntarily [196]. Yet, an exercise-induced decrease in VATMS does not mean that the origin is solely supraspinal i.e. occurring at or upstream of the motor cortex [63,196] and deficits may still occur at the spinal level. Nevertheless, supraspinal fatigue is defined as an exerciseinduced decline in force caused by suboptimal output from the motor cortex [62]. Calculating VATMS is more complicated than calculating VA with motor nerve stimulation because it is not appropriate to normalise the TMS-evoked SIT during a MVC to the resting twitch evoked by the same stimulus [63]. Since cortical and motoneuronal excitability are much lower at rest than during a voluntary contraction, the output evoked by TMS of the motor cortex cannot be compared between resting and active conditions [44,202]. This issue is circumvented by estimating the amplitude of the resting twitch rather than measuring it directly, by extrapolating the linear relationship between SIT and voluntary force at forces between 50—100% MVC [195]. The y-intercept is then taken as the estimated resting twitch (ERT) and is used in the calculation of VA. This method was pioneered in the upper limb [196,195] and was later determined to be reliable in the knee extensors [69,175], although there remain a number of methodological considerations [197]. It is not appropriate to quantitatively compare VA (measured with motor nerve stimulation) to VATMS for a given muscle due to differences in, for example, the SIT to voluntary force relationship between the two types of stimulation. The SIT measured with TMS has a linear relationship with force above 50% MVC [69,175,195], whereas the relationship is curvilinear with motor nerve stimulation at high contraction strengths (75% MVC) [59]. There may also be differences in the activation of



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Fatigue & Exercise tested and non-tested muscles, or in antagonist activation (where the magnetic field is not focal enough) [5], although coactivation is less problematic in the knee extensors. Single-pulse TMS of sufficient intensity stimulates the axons of both pyramidal neurons and (excitatory and inhibitory) cortical interneurons within the cortical area under the site of stimulation [43,169]. The volley of excitation travels down the corticospinal pathway and can be recorded in a target muscle-using surface EMG (the motor evoked potential, MEP). It is simplistic to causally relate a change in the MEP to a change in force, as the descending excitation evoked with TMS is unlikely to be analogous to the activation of descending pathways by volitional motor command [16]. However, the MEP can be used as a quantitative marker for state-specific changes in corticospinal excitability [13,16,162]. The MEP is normalised to the maximal M-wave (Mmax ) elicited during the same level of contraction and nearby in time so that MEP/Mmax reflects the balance of all facilitatory and inhibitory inputs at the cortical and spinal levels [74]. Other TMS-evoked measures include the motor threshold and cortical silent period (CSP), which reflect the axonal excitability of neuronal elements activated by TMS [45,213] and GABA-mediated intracortical inhibition [29,82,159], respectively. In addition to single-pulse TMS, stimulation paradigms including paired and triple pulse TMS can be used to probe intracortical excitatory and inhibitory circuits, and their interactions, respectively (reviewed in [159]). In addition, corticospinal axons can be stimulated at the level of the cervicomedullary junction to measure motoneuronal excitability (reviewed in [185]).

Limitations of the classical measurement of exercise-induced fatigue Measurements of fatigue in isometric vs. dynamic mode It is well-understood that exercise-induced fatigue is taskdependent. That is to say that the rate, magnitude and mechanisms of fatigue are dependent on the characteristics of the contractile activity [58] including the duration/intensity, the mode of contraction and/or the exercising muscle mass [161,160]. Furthermore, the methods used to measure a motor deficit (i.e. a reduction in force or power) can alter our interpretations of fatigue. One of the primary limitations of the classical measurement of exercise-induced fatigue is that a single-limb isometric MVC performed before and after a fatiguing task may not be adequately representative of the recruitment of neural pathways in the fatiguing task itself, particularly when the task involves whole-body exercise. In this case, the MVC does not reflect bilateral and dynamic movements which may involve a range of shortening and lengthening velocities. To overcome this limitation regarding a lack of task specificity, a number of studies have used isokinetic sprints to measure a reduction in peak power following a cycling task performed on the same ergometer, in combination with EMG to make inferences about muscle activation (e.g. [33]). The assessment of change in the force-velocity relationship, including maximal velocity, provides additional information in the assessement of exercise-induced fatigue. Few studies have examined the effect of fatiguing tasks on both maximal velocity and force. While some have indicated

5 that task failure is accompanied by greater reductions in maximal velocity than force [30,31,40], other studies have demonstrated the opposite [36,85,153]. Similarly, different recovery patterns have been observed between these two parameters after fatigue induced by concentric isotonic contractions [30,31]. The decrease in maximal velocity at task failure is likely related to metabolic alterations such as an increase in intracellular [ADP] and [H+ ], and increased myosin phosphorylation, which can recover quickly, whereas the decrease in force is mainly related to E-C coupling failure, which takes longer to recover [30,31]. For instance, greater decreases in maximal force and power than maximal velocity were observed following fatiguing single-limb contractions, and only maximal force had not recovered fully 10-min post exercise [36]. However, when fatigue is induced by eccentric contractions, there is a slow recovery in velocity-dependent power, which may be more related to E-C coupling impairments due to muscle damage, than metabolic pertubations [153]. In summary, it is important to note that neuromuscular fatigue is task dependent and there are differences in both the fatigue and recovery kinetics between measures of maximal force, power and velocity.

The time-delay from exercise cessation to the measurement of neuromuscular fatigue The time-delay from exercise cessation to neuromuscular assessment typically ranges from 45 s to 2.5 min [199], although longer delays have been reported [157,165]. Some neuromuscular responses recover rapidly post exercise. For example, following a 90-s MVC in the first dorsal interosseous, fast recovery of VA and partial recovery of twitch force has been demonstrated [184]. Rapid recovery of TMS-evoked excitability measures has also been reported [189]. More recently, one study made an informative measure of the speed of recovery in the lower limb [60]. Following repetitive knee extension—flexion exercise, significant recovery of potentiated twitch/doublet/tetanus force and MVC was found within 1—2 min following exercise cessation. For instance, quadriceps twitch force recovered from ∼ 35% of pre-exercise values to ∼ 55% in 2 minutes. As explained above, single-joint isometric tasks are of interest to examine the causes of neuromuscular fatigue during and immediately after exercise as the fatiguing exercise and the fatigue measurements are performed on the same aparatus where a time-delay can be avoided. Yet, since this type of exercise is not performed by athletes or patients in real-life contexts, fatigue should also be measured during dynamic exercise involving large muscle mass. During a traditional neuromuscular fatigue evaluation for wholebody exercise, participants perform pre-exercise measures to determine a baseline and the comparison is typically made with a neuromuscular evaluation performed when the fatiguing task is terminated (e.g. [70]). This provides information about the global effect of the task; however, it does not allow for any insight about the alterations during the exercise. This pre-to-post-exercise model is the most common type of evaluation method for locomotor tasks such as cycling and running, where it is necessary to transfer the participant from a treadmill or ergometer to a dynamometer or other apparatus equipped for the measurement of force. This method has been employed in whole-body exercise of



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Figure 1 Advantages and problems of measuring fatigue during isolated vs. whole-body (locomotive) exercise. This underlines the need for a new ergometer to assess fatigue that combines the advantages of each method. TMS: transcranial magnetic stimulation; CM: cervicomedullary; EMG: electromyography.

durations ranging from ≤ 30 s sprints (e.g. [54,198]) to ultraendurance exercise bouts lasting > 10 h (e.g. [124,192]). The advantages and problems of each method (isolated vs. whole-body exercise) are depicted in Fig. 1. Alternatives to the classical measurement of exercise-induced fatigue for whole-body exercise An improvement on the classical pre-post evaluations is to include intermediate evaluations i.e. at time-points within the fatiguing protocol. Studies employing these techniques have predominantly used isometric (e.g. [12,75]) or dynamic (e.g. [60]) single-limb exercise. Other studies have examined intermediate time points for some parameters (i.e. MVC, EMG) but not the key markers of central and peripheral fatigue, specifically VA and evoked forces, respectively (e.g. [92,178]). Few studies investigating whole-body exercise have performed intermediate neuromuscular evaluations during the task [42,87,88,116,148,158]. Despite the benefits of fatigue assessment at time-points within a whole-body exercise bout, the recovery of fatigue during the time-delay from the transfer from ergometer to chair is a valid concern [2], and may result in a loss of information concerning the magnitude and the etiology of fatigue. Indeed, due to the rapid recovery of fatigue parameters, it is essential that intermediate measures (and those at task failure) are made as soon after the interruption of whole-body exercise as is possible. Recently, our laboratory developed an innovative cycle ergometer (Fig. 2) that eliminates the need to transfer participants between the cycle ergometer and dynamometer since the apparatus is equipped for both bilateral cycling exercise and isometric force measurements in the knee extensors. In addition to the typical cycling mode, the pedals can be locked instantly in a fixed position, comparable to the standard position used during isometric evaluation.

Figure 2 Schematic representation of an innovative cycle ergometer used to assess neuromuscular fatigue during cycling exercise. The pedal position is lockable and the transition from cycling to an isometric maximal voluntary contraction of the knee extensors at ∼ 90◦ occurs in ≤ 1 s. The arrow indicates the direction of applied force.

In other words, the participant attempts to extend the lower-leg directly forward while the hip, knee and ankle angles are all ∼ 90◦ and the participant is secured at the hip and chest by non-compliant straps. With this set-up, participants cycling can be interrupted and within 1 s the ergometer pedals can come to a complete stop in the designated position for isometric evaluations. Isometric force can then be measured during voluntary and evoked contractions by a previously validated wireless pedal-force analysis system located between the pedal and the crank [180].



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Fatigue & Exercise Additionally, other parameters can be measured during the cycling exercise such as dynamic force, maximal velocity and power.

Determining factors of non-local fatigue The effects of a fatiguing task on voluntary force production and corticomotor responses are not constrained to the exercising muscles [10,90,115,152]. Several studies have shown that the fatiguing exercise in one limb can impair motor performance in the contralateral homologous or heterologous muscle group; a phenomenon which is known as ‘‘cross-over’’ or ‘‘non-local’’ fatigue [77]. For instance, sustained or repetitive single-limb contractions to task failure were deteriorated in the non-exercising muscle(s) following single-leg knee extensor exercise to exhaustion [10,76,200]. In the absence of alterations in the muscle contractile properties or M-waves, the deterioration of motor performance in the non-exercised muscle groups has been attributed to centrally-mediated factors [46,176]. Although this concept is still under investigation, it has been hypothesized that exercise-induced fatigue in the exercising muscle groups may activate an inhibitory signalling pathway in areas upstream of the primary motor cortex that ultimately reduces central motor command to the unexercised muscles [90,170]. For instance, it has been shown that when lower limb exercise was preceded by fatiguing upper limb exercise, lower limb performance (time to task failure) was reduced, but associated with less (rather than more) peripheral fatigue, and an accelerated increase in RPE [84]. The same attenuated peripheral fatigue at volitional exhaustion has been found when a unilateral-leg exercise was preceded by fatiguing exercise on the opposite leg [10]. Thus, while non-local fatigue was initially attributed to an accelerated development of peripheral locomotor muscle fatigue secondary to faster intramuscular metabolite (e.g. extracellular K+ , H+ ) accumulation, these studies show that upper body or contralateral exercise might reduce lower body exercise tolerance by accelerating the attainment of an intolerable level of sensory perception. The decline in performance may be related to the interaction of several factors including: • a reduction in motivation to perform sustained or repetitive tasks to volitional exhaustion due to sensations of fatigue in the exercised muscles (a psychological factor) [76]; • a reduction in central motor output due to activity of type III/IV muscle afferent feedback (a homeostatic factor) [11]; • an increase in intracortical and interhemispheric inhibition mediated through transcallosal connections (a neurophysiological factor) [46,176]. A combination of these mechanisms can activate inhibitory neural circuitry in the brain, which may reduce central motor command to the non-exercised muscle [10,176]. In contrast to submaximal sustained or repetitive single-limb contractions, the ability to produce maximal force in the non-exercised limb following unilateral fatiguing tasks appears to be unaffected [10,49,90,91,123]. The

7 maintenance of MVC force in non-local muscle(s) may be due to the ability to maintain cortical motor output during brief contractions. In line with this explanation, some studies exhibited an increase in responsiveness of corticospinal pathway (evident in the enhanced MEP amplitude) during brief MVCs performed by contralateral non-fatigued muscles [2,3]. The facilitation observed in the corticomotor responses was suggested to be a compensatory mechanism originating from brain circuitries controlling motor programming of the non-fatigued muscles to overcome the existing sensation of fatigue and maintain voluntary central drive to non-exercised muscles [15,16]. In summary, the current literature suggests that non-local fatigue occurs with submaximal sustained or repetitive contractions due to psychological, homeostatic and/or neurophysiological inhibitory mechanisms in the corticomotor system.

Part 2: etiology of acute lower limb fatigue Some studies have investigated lower limb fatigue using the classic 2-min sustained isometric MVC (e.g. [90]) and showed that both central (decrease in VA) and peripheral (twitch reduction by ∼ 70%, personal unpublished data) factors can explain the large decrease in MVC. However, while these studies are of interest to examine the fundamental causes of fatigue in a well-controlled environment, the present paper focuses on fatiguing tasks more relevant to daily living in humans. Another non-physiological characteristic of sustained MVCs is the fact that muscle blood flow is likely to be completely occluded during the task [167]. We will thus discuss below the causes of fatigue during dynamic intense and prolonged exercise.

High-intensity exercise Numerous studies have examined the effects of highintensity exercise on fatigue (e.g. [103,194,199]). An important introductory remark about these studies, including our own work, is that the nature of the task is likely to make the recovery process faster than for lower intensity, prolonged exercise (see later section) so that the traditional delay taken to assess fatigue precludes an accurate determination of fatigue etiology. Nevertheless, it is clear that high-intensity exercise induces substantial peripheral fatigue [80,103] and that central fatigue becomes increasingly predominant as exercise duration increases (e.g. [61]). One reason may be the alteration of the action potential propagation. Indeed, supramaximal exercise is only possible if motor unit discharge rates are elevated, which may induce an accumulation of extra-cellular K+ , which in turn induces a reduction of sarcolemmal excitability. Indeed, while it is well-known that force is higher at 100 than 20 Hz due to temporal summation, it has been shown that changing from high — (100 Hz) to low — (20 Hz) frequency stimulation in a fatigued muscle resulted in an increase in force [88]. Indeed, when switching to low frequency, there is probably sufficient time between action potentials for the normal extracellular cation concentrations to be re-established, so that the excitability of the muscle fibre membrane can at least partially recover.



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For decades, protons have been presented as the main cause of muscle fatigue during high-intensity exercise. This was thought to be due to their deleterious effects on: • ryanodine receptor response; • binding to troponin; • cross-bridge kinetics. More recent experiments have nevertheless shown that the role of acidosis is less pronounced when measured at physiological temperatures [206] and that, instead, the increased Pi due to PCr breakdown may have a key role in skeletal muscle fatigue at high-intensity. Increased Pi may: • enter the sarcoplasmic reticulum, which may result in Ca2+ -Pi precipitation and hence decrease the Ca2+ available for release; • act directly on ryanodine receptors; • prolong the time that cross-bridges are in a weak state. It has actually been suggested that lactic acid may protect against fatigue in isolated rat skeletal muscle, probably by counteracting the depressing effects of elevated [K+ ] on muscle excitability [140]. Nevertheless, it is likely that acidification still has some role in fatigue and performance deterioration. Firstly, it down-regulates glycolysis, in particular phosphofructokinase activity. Secondly, it has been shown that buffering agents can improve performance (e.g. [18]). While one reason might be accelerated oxygen uptake kinetics [214], another plausible explanation is that the reduction of acidosis attenuates type III and IV muscle afferent response, i.e. limits the discomfort from high-intensity exercise and/or central drive reduction. In other words, the deleterious role of acidosis may be more central than peripheral. This is supported by the existence of a non-linear relationship between pH and maximal EMG [93], the latter factor being used as a surrogate of central drive.

Prolonged exercise Neuromuscular function is perturbed during endurance and ultra-endurance exercise. This has been extensively demonstrated in muscles fundamental to running and cycling (i.e. knee extensors and plantar flexors). Neuromuscular changes present primarily as large decreases in maximal voluntary strength in the leg muscles. In the knee extensors, strength loss has been observed to increase with exercise time to a maximum of ∼ 40% of pre-exercise values in running events lasting > 18 h [122]. There is now general agreement that a decrease in central drive to the active muscles occurs following prolonged [87,105,148] and ultra-endurance exercice [116,192], determined as a reduction in VA assessed using the ITT (up to 30%, [116]). Recent investigations have also identified an important supraspinal component of central fatigue that develops during prolonged running and cycling bouts [87,192]. Despite the increasing body of work indicating that the brain plays a greater role in the development of central fatigue as locomotive exercise duration increases, changes at the motoneuronal level (e.g. those assessed by employing the use of spinal stimulation) of the central component of fatigue remain to be investigated. One

potential mechanism that would also explain the greater central fatigue after prolonged running compared to prolonged cycling would be the Ia disfacilitation. Changes at the peripheral level of the neuromuscular system also play a significant role in the development of fatigue during prolonged exercise bouts. Large decreases in evoked force responses (i.e. twitch, doublets, tetanic stimulation) have been observed following prolonged running [116,157,191] and cycling [87,105]. Other indices of peripheral fatigue such as changes in M-wave characteristics (i.e. used as a surrogate for changes in sarcolemmal propagation) are equivocal, with some studies having observed increases, decreases or no change in the size and duration of the M-wave [87,88,116,148,192]. Although a couple of studies have reported that prolonged exercise only induces central fatigue (e.g. [158]), both cycling [87,105] and running [116] studies examining fatigue at multiple time points propose that peripheral fatigue manifests either earlier or at the same time as central fatigue. Furthermore, Jubeau et al. [87] observed central fatigue manifesting prior to supraspinal fatigue, suggesting deficits at the level of the brain only become apparent when exercise is prolonged. These findings are consistent with the large observed decreases in VA assessed with both peripheral nerve stimulation and TMS following ultra-endurance exercise bouts [116,192].

Part 3: acute vs. chronic fatigue Potential role of low acute fatigue resistance in subjective chronic fatigue The sections above have underlined the complexity of exercise-induced fatigue etiology, especially when considering the task dependency of fatigue. Yet, chronic fatigue experienced by athletes (i.e. overtraining) or patients is even more complex. Indeed, in addition to the objective and direct physiological and biological causes of fatigue (e.g. anemia), other indirect causes of fatigue such as psychological (e.g. depression, anxiety), nutritional, social and behavioural (in particular sleep disorders) factors may explain the perceptions of chronic fatigue. The multiplicity of factors makes chronic fatigue unlikely to be due to a single cause. It is also very probable that fatigue experienced by each patient is specific to the individual. As a result, the treatment must be personalized, e.g. the training intervention known to relieve fatigue in various pathologies [23,22,35,127] should also be tailored to the causes of fatigue. Exercise physiologists have a key role to play in this context. Before focusing on chronic fatigue in two specific diseases, i.e. cancer and multiple sclerosis, in the following two sections, we would like to address here the following question: does the deteriorated resistance to acute exercise partly explain the chronic fatigue subjectively felt in clinical populations. Although to the best of our knowledge, such evidence has yet to be elucidated, there is logical reasoning behind the proposition. Indeed, as shown in Fig. 3A, a deteriorated fatigue resistance to acute exercise can lead to a greater reduction in functional capacity which in turn can require a longer recovery time. One has to perform certain physical tasks each day (e.g. going to



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Figure 3 Schematic representation of the potential deteriorated fatigue resistance to acute physical activity in chronic fatigue (panel A) and fatigue accumulation with repeated physical tasks (panel B).

the grocery store, house cleaning, going out with the children, etc.) and these repeated physical tasks can lead to fatigue accumulation (Fig. 3B). While the fatigue accumulation may not be of a magnitude to directly challenge the capacity to perform the tasks at the time, it may have two indirect consequences that can contribute to chronically perceived fatigue. First, the deteriorated fatigue resistance may induce higher metabolic disturbances, triggering nociceptive responses from the group III and IV afferent fibres (see ‘non-local fatigue’ and ‘fatigue for high intensity exercise’ sections) [151]. Second, greater levels of peripheral fatigue induce higher motor unit recruitment to perform a given submaximal task. The increased central drive could induce a corollary discharge of the efferent signal to the somatosensory cortex, which could increase the perception of effort during exercise [113,132].

Chronic fatigue: examples of cancer and multiple sclerosis Cancer-related fatigue Fatigue associated with cancer or cancer treatment has been defined as a distressing, persistent sense of physical, emotional, and/or cognitive tiredness or exhaustion that is not proportional to recent activity and interferes with usual functioning [15]. It is well accepted in the field that cancerrelated fatigue (CRF) is likely dependent on a number of mechanisms, but the etiology is unresolved [129]. CRF is reported to be the most common and disturbing symptom in adults with cancer [208]. Furthermore, the effects of CRF can be long-lasting as approximately one-third of cancer survivors who have completed primary treatment and/or are in clinical remission experience severe and persistent fatigue for a number of years post-treatment [4,20,128]. In addition to a profound reduction in QoL [20], CRF results in increased utilization of health care resources [68], prevents the return to work and reduces the capability to work [83]. As a subjective symptom, CRF is typically assessed via self-report questionnaires (e.g. [14,21]). Primary care clinicians are guided to treat comorbid factors such as anemia, sleep disturbance, mood disorders and pain [21,164]. In the absence of such identifiable factors, there is minimal evidence to support the effectiveness of pharmacological interventions for CRF in cancer survivors [16]. These considerations,

alongside increasing five-year survival rates [26], highlight CRF as a priority for future research [14]. A number of causal mechanisms of CRF have been proposed [129,166]. In regards to objective measures, there are biomarkers that can be evaluated as indicators of pathogenic processes related to CRF. Recent systematic reviews have described the current understanding of the biology of CRF [168] and its genomic variants [186], and highlight the contribution of multiple processes including proinflammatory cytokine and immune response pathways. In addition, there are numerous neuromuscular complications associated with cancer and its treatment [72], but the relationship with CRF remains unclear. For example, there has been progress in the understanding of the molecular mechanisms of cancer cachexia, which is characterised by general muscle atrophy [119]. However, the functional impairment (loss of muscular strength/muscle weakness) is not fully explained by loss of muscle mass (which can be examined using specific force i.e. force normalised to cross sectional area) and may instead be due to neuromuscular deficits related to CRF [67,154]. A number of studies have provided evidence to support these neuromuscular alterations in fatigued cancer survivors [24,95,96,130,137,210]. In a pilot study that aimed to address the central and peripheral mechanisms of exerciseinduced fatigue, cancer patients with CRF (> 4 weeks post-treatment) performed a sustained submaximal isometric contraction of the elbow flexors [210]. In comparison to age- and sex-matched controls, the cancer group had a lower baseline MVC and interestingly, lower M-wave amplitude, suggesting an impaired neurotransmission, which was unaltered by the fatiguing task. The cancer group terminated the task earlier, but with less evidence of peripheral fatigue at volitional exhaustion. Although, this finding was corroborated by later studies using similar experimental designs in this muscle group [95,96], the functional relevance of the elbow flexors is questionable in regards to activities of daily living. Indirect evidence including a greater SIT amplitude prior to task disengagement [210], less disturbance to muscle contractile properties [95,210] and less myoelectrical evidence of muscle fatigue (via voluntary EMG) [96] suggests a greater contribution of central fatigue in limiting submaximal motor activity in cancer patients with CRF. In contrast, one study found no differences the reduction in MVC or VA in fatigued vs. non-fatigued breast cancer survivors following a sustained contraction of the knee extensors at 30% MVC [137]. However, the authors noted that the study might



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10 not have been sufficiently powered to detect such differences. Overall, the neuromuscular correlates of CRF are not well elucidated and those studies that have used neurostimulation are methodologically limited in comparison to current standards in the field [125]. To date, no studies have utilised TMS to explore the corticospinal correlates of CRF. In addition, the proposed central contribution to motor task failure has only been inferred from indirect measures that do not directly quantify central fatigue [95,96,210]. Currently, there are insufficient data to conclude that there is relationship between chronic and exercise-induced fatigue in cancer survivors but further research in this area is warranted. Studies investigating exercise-induced fatigue in cancer patients have been limited only to tasks involving single-limb, sustained isometric contractions. No studies have investigated neuromuscular fatigue in a whole-body, dynamic activity as relevant to daily activities, rehabilitation and locomotion. However, whole-body exercise capacity has been studied in fatigued and non-fatigued cancer survivors [137]. In line with lower self-reported levels of moderate to vigorous exercise, age-adjusted peak oxygen uptake and power at lactate threshold were both lower in the CRF group. Based on these data, it was hypothesized that persistent fatigue may be related to an individual reaching or exceeding lactate threshold during activities of daily living [137], but this has yet to be tested empirically. Aerobic exercise interventions are beneficial in the management of CRF both during and after treatment [35]. The improvement in self-reported fatigue with exercise may be partly mediated by behavioural factors [7,156], and is unlikely to be due to a simple biological or psychosocial explanation [128]. However, given the improvement in CRF with exercise interventions, a comprehensive evaluation of the mechanisms of exercise-induced fatigue in fatigued vs. non-fatigued cancer survivors would be a valuable addition to current knowledge. An alteration in the central nervous and/or muscular system leading to early neuromuscular fatigue development with physical activity is a viable mechanistic target for therapeutic intervention. As explained above, the goal would ultimately be to implement a tailored exercise intervention to alleviate CRF, promote physical well-being and improve QoL in cancer survivors. Further research using the methods to evaluate exerciseinduced fatigue as discussed earlier in this review, and in combination with self-report measures of CRF, is therefore advocated.

Fatigue in multiple sclerosis Fatigue in multiple sclerosis (MS) is one of the most common [99,106] and disabling [66] symptoms of this progressive neurodegenerative disease. MS-related fatigue has been defined as a ‘‘subjective lack of physical and/or mental energy that is perceived by the individual or caregiver to interfere with usual and desired activities’’ [136]. However, varying definitions have been proposed [163], including those that extend beyond a description of the subjective experience in a medical setting [126]. MS-related fatigue has a significant impact on daily life in that it is related to a reduced QoL, physical function and emotional well-being [55] and can be predictive of disease worsening [27]. Fatigue in MS is associated with comorbidities such as depression,

R. Twomey et al. irritable bowel syndrome and migraines [56], which are likely to impact the subjective experience of this multifactorial phenomenon. Similarly to CRF, the clinical assessment of MS-related fatigue relies on self-report questionnaires [57,100], although objective measures of ‘‘motor fatigue’’ involving kinematic gait analysis have been explored [135,173]. While self-report measures may capture the perceptions of fatigue, it is also important to consider that exacerbated fatigue during motor tasks may reduce the capacity of an individual to perform activities of daily living [163]. In contrast to the research in CRF, numerous studies have assessed the neural correlates of perceived fatigue in MS [28,211]. Abnormal patterns of cortical activation in MS [155] and dysfunction in specific cortical and subcortical regions related to brain networks thought to be involved in MS fatigue [28] have been shown by neuroimaging studies, but these are outside the scope of this review. Many studies have used TMS to investigate neurophysiological abnormalities in MS [28,211]. The majority of studies report a reduced MEP amplitude and prolonged central motor conduction time (indicative of a reduced corticospinal excitability) in comparison to controls [211]. However, relatively few studies have assessed the relationship between TMS-evoked responses and sensations of fatigue measured using self-report tools. In the studies which have investigated high vs. low self-reported fatigue in people with MS (PwMS), there is currently poor evidence of an association between corticospinal excitability and perceived fatigue (e.g. [108,131,146]) but it is difficult to draw conclusions as MS is highly heterogeneous and findings are likely to be mediated by MS disease course and severity. Many studies have investigated objective fatigue measures in the upper limb in PwMS. For example, using the ITT described earlier, Sheean et al. [174] showed that excessive neuromuscular fatigue in PwMS (vs. a control group) was of central origin since a more pronounced reduction in VA of the thumb abductors was found following a 45-s sustained MVC, suggesting that central fatigue contributes to the symptom of fatigue in this population [181]. In the few studies to date, which have measured exercise-induced fatigue and/or TMS responses in the lower limb, the majority has used the ankle dorsiflexors [94,139,172,193]. Ng et al. [139] found greater voluntary EMG activity in the TA during graded isometric dorsiflexor contractions from 10—70% MVC, in comparison to controls at a similar relative and absolute force [139]. The EMG/force relationship correlated with disability status and the authors speculated that a chronically increased central motor drive during low-intensity contractions could contribute to symptoms of fatigue in PwMS. However, voluntary EMG as a measure of neural drive comes with inherent methodological limitations [52,53] and should be interpreted with due caution. Another study reported a lower baseline MVC force and a more pronounced reduction in force following a dynamic single-limb fatiguing protocol (5 bouts of 15-s foot tapping as fast as possible) in PwMS in comparison to controls [193]. Between foot tapping bouts, resting TA MEP amplitude increased to a greater extent in the MS group and this was suggested to reflect a change in the balance of intracortical inhibitory and excitatory processes directed at maintaining task performance as fatigue develops.



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Fatigue & Exercise PwMS have reduced whole-body exercise capacity vs. healthy controls and those with chronic fatigue have a slower recovery of perceived leg fatigue after cycling exercise [38]. However, no studies have investigated exercise-induced fatigue after whole-body exercise in PwMS. Due in part to a complex and poorly understood pathogenesis [81], non-pharmacological treatment options for fatigue in MS are not well established [204]. As for CRF, exercise training is beneficial in the management of MS [22,134], although the reasons are not well understood and as such, warrant further investigation.

Conclusion In clinical populations where chronic fatigue is particularly pervasive, debilitating and mechanistically complex, we propose that the relationship between the central and peripheral contributions to neuromuscular fatigue and the perceptions of fatigue measured using self-report questionnaires warrants further investigation. There are a number of alternatives to the classical measurement of exerciseinduced fatigue, which could be utilised in this framework to overcome some of the enduring methodological limitations. It is acknowledged that chronic fatigue is likely to be specific to the individual and unlikely to be due to a single or homogenous biological or psychosocial explanation. Although reduced fatigue resistance and chronically perceived fatigue are distinct concepts, there is evidence to support exercise as a non-pharmacological intervention for the alleviation of the sensations of fatigue and/or for overall disease management in certain clinical pathologies. Exercise physiologists have a key role to play to optimise these training interventions. Tailored exercise programmes based on the neurophysiological correlates of early task disengagement from whole-body exercise, alongside a comprehensive evaluation of contributing factors such as sleep disturbance, are a potential target for therapeutic intervention in the study of this multifaceted and devastating symptom.

Declaration of interest The authors declare that they have no competing interest.

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