1. Introduction

2. Peripheral Processes in Muscle Fatigue

3. Central Processes in Muscle Fatigue

3.2. Spinal Muscle Fatigue in Health

3.2.1. Motor Unit (MU) Properties as a First Line of Defense

As a first line of defense, intrinsic properties of MUs may mitigate the effects of muscle fatigue.

MU Types. One basis of force optimization during developing muscle fatigue resides in the differentiation of MUs into types of different fatigability. In cats (and humans), MUs are classified into three main types: large, strong, fast-contracting and fatiguable MUs (type FF); strong, fast-contracting and fatigue-resistant MUs (type FR); slowly contracting, fatigue-resistant (type S) MUs. During long-lasting weak muscle contractions, S-type MUs are active, while FR-type and FF-type are recruited at contractions of higher forces, where FF-type MUs fatigue relatively soon, with contraction and relaxation times increasing over time (Bączyk et al. 2022; Burke 2009).

Force Potentiation in FF-type MUs. When step-like depolarizing currents of 60 seconds duration were injected into different cat gastrocnemius MU types, S-type MUs showed only a small firing-rate adaptation and their isometric force declined hardly over time, while the FF-type MN discharge rate adapted more strongly, and so did MU force (Figure 1; see legend). Important in the latter case is the fact that FF-type MUs exhibited force potentiation between about 5 and 30 seconds after the start of current injection, compensating initially for force loss (Kernell and Monster 1982). This transitory relative force increase does not suffice to significantly prevent force loss, but must be complemented by sensory feedback from the fatiguing muscle.

Comments. The fact that skeletal muscles are built of assemblies of MUs with different mechanical and fatigue properties and the phenomenon of force potentiation in FF-type MNs are a first line of defense, but do not suffice for the CNS to control muscle fatigue. “You can only control what you sense” (McCloskey and Prochazka 1994). So sensors that monitor the events in fatiguing muscles are required. Which ones are suitable to do so?

Figure 1. Schematic illustration of the typical adaptation behaviors of MN discharge rate (A) and MU isometric force (B) of a cat gastrocnemius S-type MU (“S unit”) and a gastrocnemius FF-type MU (“FF unit”) in response to step-like, long-lasting depolarizing currents injected into the respective MNs. The red dashed curves were fitted to data from Kernell and Monster (1982; Fig. 5). These curves represent relative values and, for better comparison, were normalized to the initial values set to 100%. As obvious, neither the discharge rate (A) nor the force (B) of the S-type MU adapted very much over time. By contrast, the respective values of the FF-MU did. The lower dashed curve for FF-MU force (B) was fitted to the data during the first five seconds and the data beyond 35 seconds, and extrapolated in between. As seen, the actual recorded MU force (green dashed curve) exceeded the extrapolated values, indicating that, for about 30 seconds, the FF MU developed a potentiated force. In fact, the time course of the red fit is an estimate of the unpotentiated MU force development, as supported by independent data. Kernell and Monster (1982; Fig. 6) measured and averaged the forces of five fresh, i.e., non-fatigued and non-potentiated, type FF MUs, produced by stimulation with 1-second trains at the time-related adapted discharge rates when the unit was developing fatigue and potentiation during long-lasting depolarization. Abbreviations: FF: fast-contracting, fast-fatiguing; S: slowly contracting, fatigue-resistant.

Figure 1. Schematic illustration of the typical adaptation behaviors of MN discharge rate (A) and MU isometric force (B) of a cat gastrocnemius S-type MU (“S unit”) and a gastrocnemius FF-type MU (“FF unit”) in response to step-like, long-lasting depolarizing currents injected into the respective MNs. The red dashed curves were fitted to data from Kernell and Monster (1982; Fig. 5). These curves represent relative values and, for better comparison, were normalized to the initial values set to 100%. As obvious, neither the discharge rate (A) nor the force (B) of the S-type MU adapted very much over time. By contrast, the respective values of the FF-MU did. The lower dashed curve for FF-MU force (B) was fitted to the data during the first five seconds and the data beyond 35 seconds, and extrapolated in between. As seen, the actual recorded MU force (green dashed curve) exceeded the extrapolated values, indicating that, for about 30 seconds, the FF MU developed a potentiated force. In fact, the time course of the red fit is an estimate of the unpotentiated MU force development, as supported by independent data. Kernell and Monster (1982; Fig. 6) measured and averaged the forces of five fresh, i.e., non-fatigued and non-potentiated, type FF MUs, produced by stimulation with 1-second trains at the time-related adapted discharge rates when the unit was developing fatigue and potentiation during long-lasting depolarization. Abbreviations: FF: fast-contracting, fast-fatiguing; S: slowly contracting, fatigue-resistant.

3.2.2. Neuronal Sensors of Muscle Fatigue

Several classes of neuronal sensors and their afferent fibers could signal the muscle state during fatigue. Among them are the larger-diameter group Ia and II afferents from muscle spindles and group Ib afferents from GTOs, and smaller-diameter group II and IV afferents from free nerve endings. Muscle spindle afferents are commonly regarded as muscle length receptors, GTO as afferents muscle force receptors, and group II and IV afferents are more complex.

3.2.2.1. Fatigue-Related Changes in Firing of Muscle Spindle Afferents

In the course of fatiguing muscle contractions, human muscle spindle afferents reduced their average discharge rate, possibly due to a reduction in fusimotor drive to spindles (Macefield et al. 1991). Homonymous and synergistic MNs would thereby be disfacilitated, which could contribute to their firing rate decline. The differences in spindle discharge to the above cat data is probably due to the continuous fusimotor activation throughout the fatiguing stimulation.

Comparable results were obtained in the rat masseter muscle system. The masseter muscle was fatigued by prolonged tetanic masseter-nerve electrical stimulation. Muscle fatigue caused a decrease in the discharge frequency of masseter muscle spindle afferents in most of the examined units. Hence, fatigue signals from the fatiguing muscle, traveling through capsaicin-sensitive fibers, are able to diminish the proprioceptive input by a central presynaptic influence (Brunetti et al 2003).

The question arises whether beyond the average discharge rate of spindle afferents, their discharge fluctuation could provide valuable information on muscle state, in particular about fatigue.

Sensitivity of Spindle Afferents to Single MU Contractions. The precise temporal discharge patterns of muscle spindle afferents depend on their sensitivity to small-amplitude mechanical events in muscles, especially MU contractions Thus, in cats, muscle spindle afferents, in particular group Ia afferents, respond to single MU contractions. Hence, the contraction of a single MU can be an effective stimulus to a spindle receptor and may induce afferent firing pattern alterations similar to those observed with whole muscle contraction. There are quantitative differences in the response of a receptor to contraction of different MUs and to contraction of the same MU at different lengths. It has been suggested that, rather than simply acting as generalized force or length sensors for the muscle as a whole, each receptor’s spike train carries information about the state of a particular set of MUs (Binder et al. 1976). The quality of this information of course depends on the activity of many MUs on an afferent. Thus, by simultaneously stimulating multiple α-axons with different uncorrelated patterns and recording from multiple group Ia fibers, post-stimulus time histograms (PSTH) revealed widely graded influences of single MU contractions on different muscle spindles, as described above. But in most instances, the signal transmission from a single MU to a single Ia fiber was disturbed to varying degrees by concomitant activity from other MUs (Schwestka et al. 1981). Nonetheless, using the same stimulus paradigm, contractions of single MUs were reflected in membrane potential changes of homonymous α-MNs (Koehler et al. 1984). What is the relevance to muscle fatigue signaling? Using the same approach as Schwestka et al (1981), time-domain (PSTH) and frequency-domain (gain) computations were performed to study the effects of fatiguing muscle-unit contractions on the signal transmission from motor efferents to spindle afferents. In the course of muscle unit fatigue, during which the gain of the force-producing sub-system decreased, the gain of the sub-system transforming force to afferent discharge increased so that the overall gain between motor efferents and spindle afferents remained relatively high. This could be a mechanism that preserves a high quality of afferent information on MU contractions (Christakos and Windhorst 1986). Still, whether under natural conditions single-unit activity patterns have an influential effect on MNs during fatigue remains in doubt.

3.2.2.2. Fatigue-Related Changes in Firing of GTO Afferents

The firing of group Ib afferents from GTOs would be expected to decrease with declining muscle force. Indeed, alterations in the stretch sensitivity of group Ib afferents have been reported in fatigued gastrocnemius muscles of cats. Group Ib afferent responses to the velocities of Achilles tendon stretch were either completely abolished or depressed over several seconds compared to pre-fatigue firing frequencies. Post-excitation depression of the group Ib receptor potential appears to be one possible mechanism (Hutton and Nelson 1986). However, how these changes would influence the reflex effects is less clear. Excitatory and inhibitory interneurons intercalated in spinal reflex pathways of group Ib afferents from GTOs receive input from group III/IV afferents (Jankowska 1992; Schomburg 1990; Figure 2) and might thus reduce their discharge with fatigue. And since group Ia and Ib afferents in part converge on the same interneurons, support from muscle spindles would be expected to also decline. In fact, in cats, excitatory and inhibitory interneurons are shared to a large extent with group II afferents and in part even group Ia afferents from muscle spindles (Jankowska and Edgley 2010). The way the discharge of these interneurons behave during muscle fatigue would depend on a delicate balance between influences. – It has been suggested that GTOs are able to monitor muscle damage resulting from repeated eccentric contractions. Such contractions cause an increase in passive muscle tension and GTO discharge (Gregory et al. 2003).

Figure 2. Rarified scheme of group III/IV afferent connections to some important spinal neurons in the cat. For simplicity, only connections from ankle extensor calf muscles are shown, while flexor muscle afferents are not. A muscle spindle is symbolized by a long black bar. For simplicity, secondary endings with their group II afferents are omitted. Spinal excitatory neurons are symbolized by open turquoise circles and their synaptic terminals by T-junctions. Inhibitory interneurons are symbolized by closed and filled purple circles, as are their synaptic terminals. Closed yellow circles symbolize either excitatory or inhibitory neurons, their synaptic terminals being symbolized by superimposed small closed yellow circles and T-junctions. Every circle symbolizes groups of neurons and synapses. Abbreviations: RC, Renshaw cell; RIaI, reciprocal Ia inhibitory interneuron (Own design; see also Windhorst 2003, Windhorst and Dibaj 2023 as well as Dibaj and Windhorst 2024).

Figure 2. Rarified scheme of group III/IV afferent connections to some important spinal neurons in the cat. For simplicity, only connections from ankle extensor calf muscles are shown, while flexor muscle afferents are not. A muscle spindle is symbolized by a long black bar. For simplicity, secondary endings with their group II afferents are omitted. Spinal excitatory neurons are symbolized by open turquoise circles and their synaptic terminals by T-junctions. Inhibitory interneurons are symbolized by closed and filled purple circles, as are their synaptic terminals. Closed yellow circles symbolize either excitatory or inhibitory neurons, their synaptic terminals being symbolized by superimposed small closed yellow circles and T-junctions. Every circle symbolizes groups of neurons and synapses. Abbreviations: RC, Renshaw cell; RIaI, reciprocal Ia inhibitory interneuron (Own design; see also Windhorst 2003, Windhorst and Dibaj 2023 as well as Dibaj and Windhorst 2024).

The same question as above for spindle afferents arises whether beyond the average discharge rate of GTO afferents, their discharge fluctuation could provide valuable information on muscle state, in particular about fatigue.

Sensitivity of GTO Afferents to Single MU Contractions. The responses of cat soleus GTOs to repetitive twitch contractions of: (i) different MUs within the muscle, (ii) single MUs at different muscle lengths, and (iii) single MUs when the pulse-train pattern of stimulation delivered to the MU axon was altered. Group Ib afferents responded to each of several hundred successive MU twitches with identical numbers of spikes and with relatively invariant latencies. GTOs are sensitive to subtle alterations in MU twitch waveform and amplitude, and this sensitivity was reflected in the precise timings of their afferent discharge. Considering the number of GTOs in a muscle, and the likelihood that every MU is connected with at least one receptor, the sensitivity of GTOs insures that every twitch of every MU will be reflected in the population of afferent signals (Binder et al. 1977).

3.2.2.3. Group III/IV Muscle Afferents

Group III/IV afferents from muscle free nerve endings are sensitive to both mechanical stimuli and metabolic and thermal changes in muscle. During fatiguing muscle contractions, they are excited by mechanical changes (Hayward et al. 1991), as well as by intra-muscular metabolic and chemical changes (Decherchi and Dousset 2003).

Mechanically Sensitive Afferents. Group III muscle afferents are more mechano-sensitive than group IV afferents during skeletal muscle contraction, force production, dynamic/static muscle stretch and local intramuscular pressure. But their response to a mechanical stimulus may be potentiated by chemical stimuli. Thus, muscle fatigue both increases spontaneous discharge in these mechanically sensitive afferents and sensitizes their response to muscle stretch, surface pressure, and, in a few instances, muscle contraction. These fatigue-induced changes occur after 5-10 min of sub-maximal fatiguing stimulation. However, the discharge of many slowly conducting mechano-receptor afferents declines during the initial phase of fatigue, which may argue against a primary role in mediating the initial decline in MN rate that is so prominent in fatiguing maximum voluntary muscular contraction (Hayward et al. 1991).

Metabolically Sensitive Afferents have been suggested to be of two sub-types. One sub-type, the so-called metabo- or ergoreceptors, only responds to innocuous concentrations of intramuscular metabolites (protons, lactate, ATP) associated with ‘normal’ (i.e. freely perfused and predominantly aerobic) exercise up to strenuous intensities. In contrast, the other subtype, the so-called metabo-nociceptors, only respond to higher (and concurrently noxious) levels of metabolites present in muscle during ischemic contractions or following hypertonic saline infusions – but not to non-noxious metabolite concentrations associated with normal exercise. The sub-types show molecular differences including the differential expression of purinergic receptors (P2X2,3,4), transient receptor potential vanilloid type 1 and/or 2 (TRPV1/2), and acid-sensing ion channels 1, 2, and 3 (ASIC 1-3) (Amann et al. 2015).

Muscle group IV afferents are more sensitive to metabolites released into the interstitium by muscle activity and their activation usually starts after a delay during prolonged muscle contraction and continues to discharge until the withdrawal of muscle metabolites (Amann et al. 2015; Decherchi and Dousset 2003; Gandevia 2001; Laurin et al. 2015; Mense 1993; Rotto and Kaufman 1988; Taylor et al. 2016).

Group III and IV muscle afferents originating in exercising limb muscles play a significant role in the development of fatigue during exercise in humans. Their activation causes effects all along the CNS. Due to their wide central distribution, they have diverse roles. They adjust heart rate, ventilation, blood pressure and vascular resistance during physical exercise, modulate spinal reflexes, and may contribute to improve muscle performance by regulating the peripheral fatigue development and by avoiding excessive muscle impairments. Feedback from group III/IV muscle afferents to the CNS reflexively increases ventilation and central (cardiac output) and peripheral (limb blood flow) hemodynamic responses during exercise and thereby assures adequate muscle blood flow and O2 delivery. This response is a key factor in minimizing the rate of development of peripheral fatigue and in optimizing aerobic exercise capacity. On the other hand, the central projection of group III/IV muscle afferents impairs performance and limits the exercising human via its diminishing effect on the output from spinal MNs which decreases voluntary muscle activation (i.e. facilitates central fatigue).

Tetrodotoxin-resistant (TTX-R) afferent fibers from rat muscles exhibit a multi-sensitive profile, including nociception. TTX-R afferent fibers play an important role in motor control, via spinal and supraspinal loops. To quantify the TTX-R afferent input, the cord-dorsum potential (CDP) was recorded, which results from the electrical fields set up within the spinal cord by the depolarization of dorsal horn (DH) interneurons, activated by an incoming volley of TTX-R muscle afferents. The changes in TTX-R CDP size before, during and after fatiguing electrical stimulation of the gastrocnemius-soleus (GS) muscle were taken as a measure of TTX-R C-unit activation. At the end of the fatiguing protocol, following an exponential drop in force, TTX-R CDP area decreased in the majority of trials (9/14) to 0.75 ± 0.03% (mean ± SEM) of the pre-fatigue value. Recovery to the control size of the TTX-R CDP was incomplete after 10 min. Furthermore, fatiguing trials could sensitize a fraction of the TTX-R C-fibers responding to muscle pinch. This suggests a long-lasting activation of the TTX-R muscle afferents after fatiguing stimulation (Kalezic and Steffens 2013).

Fatigue-induced Group III/IV Effects in the Spinal Cord. In the spinal DH, small-diameter afferents (group III or Aδ and group IV or C) contact a large variety of excitatory and inhibitory interneurons that provide for complex signal processing at spinal levels, and also connect with a minority of projection neurons that send axons rostrally. Projection neurons also produce axon collaterals that are widely distributed within and between spinal segments, whose functions are hardly known, however.

DH neurons also receive modulating inputs from higher centers.

Spinal Distributions of Group III/IV Afferent Connections. Group III/IV afferents distribute their signals in the spinal cord, as tested by Fos-immunoreactive (Fos-ir) expression and nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d)-reactive neurons upon fatiguing contractions of the cat triceps surae muscle, caused by direct intermittent high-rate (100 s^-1) electrical stimulation of the triceps surae muscle or the ventral root L5 (VRL5) for 30 min. The fatigue-related c-fos gene expression was more extensive in the L2-L5 segments on the stimulated side, and the majority of Fos-ir neurons were concentrated in the DH. After direct electrical muscle stimulation, the highest number of Fos-ir neurons were detected in two regions: layer 5, and superficial layers (1 and 2(o)), although many labeled cells were also found in layers 3, 4, 6, and 7. In response to VRL5 stimulation, the maximal density of Fos-ir neurons was detected in the middle and lateral parts of layers 1 and 2(o), the zone of termination of high-threshold muscle afferents. Fos-ir cells were also found in layers 5 and 7 on the stimulated side. A few Fos-ir neurons were found in the ventral horn (layer 8 and area 10) on both sides. The lamellar distribution of NADPH-d-reactive neurons was similar over all experimental groups of animals. In the L3-L6 segments, such reactive cells were arranged in two distinct regions: DH (layers 2(i), 3, and 5) and area 10; in the L1 and L2 segments, an additional cluster of NADPH-d positive cells was found in the intermediolateral cell column (IML). Double-labeled cells were not detected. We suggest that c-fos expression in response to muscle fatigue reveals activity of functionally different types of spinal neurons which could operate together with NOS-containing cells in pre-MN networks to modulate the MN output (Pilyavskii et al. 2001).

These data raise the possibility that muscle group III/IV afferents influence many, if not all neurons in the spinal cord (Figure 2; Windhorst 2003, 2007).

Comments. All the above sensory afferent systems have widespread distributions in the CNS, which in part are difficult to comprehend, depending on the complex biomechanics of the skeleto-muscular system (Windhorst 2021).

3.2.3. Spinal Fatigue-Related Reflexes

At spinal level, mechanically or metabolically activated group III/IV muscle afferents in cats have polysynaptic effects on α-MNs, γ-MNs and interneurons, such as reciprocal Ia inhibitory interneurons (mediating reciprocal inhibition between antagonist α-MNs), Renshaw cells (RCs) (mediating recurrent inhibition) (Figure 2). Prior to this, they are subjected to the scrutiny of presynaptic inhibition, which itself receives inputs from group III/IV muscle afferents.

3.2.3.1. Presynaptic Inhibition (PSI)

In humans, the stretch-reflex function was investigated after long-lasting stretch-shortening cycle exercise, which resulted in a clear deterioration in muscle function immediately after fatigue, which was accompanied by a clear reduction in active and passive reflex sensitivity. For the ratio of the electrically induced maximal H-reflex to the maximal mass compound AP, only one significant reduction occurred immediately after fatigue (71.2%, P < 0.01). A similar significant decrease in the stretch-resisting force of the muscle also occurred. Indirect markers of muscle damage (serum creatine kinase activity and skeletal troponin I) were increased, which could result from ultrastructural muscle damage. It was suggested that the acute reduction in reflex sensitivity was of reflex origin and due to two active mechanisms, disfacilitation and presynaptic inhibition and that the delayed second decline in the sensitivity of some reflex parameters may be attributable to the secondary injury due to some inflammatory response to the muscle damage. This might emphasize the role of presynaptic inhibition via group III and IV muscle afferents (Avela et al. 1999).

In humans, presynaptic modulation of group Ia afferents converging onto the MN pool of the extensor carpi radialis was compared during contractions (20% of maximal force) sustained to failure as subjects controlled either the angular position of the wrist while supporting an inertial load (position task) or exerted an equivalent force against a rigid restraint (force task). The results suggest a task- and time-dependent modulation of presynaptic inhibition of group Ia afferents during fatiguing contractions (Baudry et al. 2011). Also, there is evidence for effects of muscle fatigue in plantar flexors on presynaptic inhibition (Grosprêtre et al. 2018).

In adult rats, cholinergic (ACh) interneurons in DH laminae III/IV co-localized gamma-aminobutyric acid (GABA) and frequently form axo-axonic synapses with terminals of primary afferents. Therefore, they are probably last-order interneurons involved in presynaptic inhibition. Indeed, ACh interneurons receive contacts from both myelinated and unmyelinated primary afferents. Hence, ACh interneurons likely are components of an inhibitory feedback pathway that is monosynaptically activated by primary afferents (Olave et al. 2002).

In cats, the potential involvement of presynaptic inhibition was tested by conditioning the monosynaptic H-reflex by stimulation of the nerve to the posterior biceps and semitendinosus (PBSt) muscles. The intensity of presynaptic inhibition as measured by the reduction of the normalized value of monosynaptic reflex amplitude during conditioning, increased as compared to the pre-fatigue state, followed by a recovery. Both primary afferent depolarization (PAD) and the intensity of antidromic discharges in primary afferents increased with the presynaptic inhibition intensity. This demonstrated a fatigue-related suppression of group Ia excitation of synergistic MNs, probably arising from the activation of group III/IV afferents (Kalezic et al. 2004).

Rather than indirectly measuring H-reflexes, more direct monosynaptic reflex effects can be measured by intracellular recordings from MNs. In cats, responses of GS MNs to stretches of the homonymous muscles were recorded intracellularly before, during and after fatiguing stimulation (FST) of GS muscles. VRs L7 and S1 were cut, and FST was applied to VR S1, a single FST session including 4 to 5 repetitions of 12s periods of regular 40/s stimulation. Muscle stretches consisted of several phases of slow sinusoidal shortening-lengthening cycles and intermediate constant lengths. The maximal stretch of the muscles was 8.8 mm above the rest length. Effects of FST on excitatory postsynaptic potentials (EPSPs) and APs evoked by the muscle stretches were studied in 12 MNs. Stretch-evoked EPSPs and firing were prominently suppressed after FST, with the exception of a post-contraction increase of the first EPSP after FST, which was most likely due to after-effects in the activity of muscle spindle afferents. The post-fatigue suppression of EPSPs and spike activity was followed by restoration within 60-100 s. Additional bouts of FST augmented the intensity of post-fatigue suppression of EPSPs, with the AP activity sometimes disappearing completely. FST itself elicited EPSPs at latencies suggesting activation of muscle spindle group Ia afferents via stimulation of ß-fibers. The suppression of the stretch-evoked responses most likely resulted from fatigue-evoked activity of group III and IV muscle afferents. Presynaptic inhibition could be one of the mechanisms involved, but homosynaptic depression in the FST-activated group Ia afferents may also have contributed (Kostyukov et al. 2005).

In cats, the magnitude of reflex inhibition, induced in the soleus muscle by contraction or stretch of the medial gastrocnemius (MG) muscle, was substantially increased during and after electrically induced fatigue of the MG (Hayward et al. 1988).

Presynaptic inhibition could thus contribute to the reduction of proprioceptive input to MNs because it is subject to group III/IV afferents from fatiguing muscles.

Comments. Different motor tasks may require different patterns of proprioceptive feedback to regulate spinal motor control functions. Presynaptic inhibition (PSI) as a guard at the spinal input gate is an adaptable mechanism to control the inflow of sensory inputs, in particular from groups Ia, II, Ib, cutaneous and other afferents, which may presynaptically inhibit each other. The interneurons mediating PSI may be excited or inhibited in various proportions by group II to IV afferents, cutaneous and joint afferents, by signals descending in cortico-spinal (CST), rubro-spinal (RST), reticulo-spinal (ReST) and vestibulo-spinal (VST) tracts, nucleus reticularis gigantocellularis, as well as by serotonergic (5-HT) raphé-spinal and noradrenergic (NA) locus coeruleus (LC) systems (Jankowska 1992; Quevedo 2009; Rudomin 2009; Rudomin and Schmidt 1999).). In animals and humans, PSI can be set to different mean levels and modulated dynamically during rest, locomotion and voluntary movements. For example, the monosynaptic transmission from group Ia afferents to  -MN is presynaptically inhibited more strongly during stance than rest (lying), and more strongly during running than walking (Katz et al. 1988; Nardone and Schieppati 2004).

3.2.3.2. Monosynaptic Group Ia Afferent Excitation

H-reflex. In humans, the soleus muscles were fatigued under ischemic conditions by intermittent stimulation at 15 Hz. The excitability of the soleus MNs, tested using the H-reflex, was significantly reduced during fatigue. Control experiments with ischemia or electrical stimulation, but without fatigue, failed to demonstrate any significant effects on reflex excitability. This favored the view of reflex inhibition of α-MNs during fatigue (Garland and McComas 1990). H-reflex depression also occurred during low-force fatigue. Eleven healthy subjects performed fatiguing contractions of low force (25% MVC) or high force (42-66% MVC). H-reflexes, muscle compound APs (M-waves), twitch contractile properties, and MU discharges were recorded from the soleus muscle. In the low-force fatigue task, MU firing rate increased gradually over time, whereas the resting H-reflex was significantly depressed at 15% of endurance time and remained quasi-constant for the rest of the task. This suggests that, during a low-force fatigue task, the processes mediating the resting H-reflex depression are relatively independent of those modulating the MU firing rate. In the high-force fatigue task, a decline in the average MU discharge rate was accompanied by a decrease in the resting H-reflex amplitude and a prolongation of the twitch half-relaxation time (HRT) at the completion of the fatigue task (Kuchinad et al. 2004).

In decerebrate cats, changes in the monosynaptic H-reflex of GS MNs were studied after fatiguing stimulation of the GS muscles. Monosynaptic reflexes were evoked by stimulation of Ia fibers in the GS nerve and recorded from a filament of ventral root (VR) L7. Intermittent 40/s stimulation for 10-12 minutes was applied to the distal part of the cut VR S1. The potential involvement of recurrent inhibition and presynaptic inhibition was tested by conditioning the monosynaptic reflex by stimulation a filament of VR L7 or of the nerve to the PBSt muscles, respectively. The intensity of presynaptic inhibition as measured by the reduction of the normalized value of monosynaptic reflex amplitude during conditioning, increased as compared to the prefatigue state, followed by a recovery. In contrast, the intensity of recurrent inhibition first diminished and then gradually recovered. Both PAD and the intensity of antidromic discharges in primary afferents increased with the presynaptic inhibition intensity. This demonstrated a fatigue-related suppression of group Ia excitation of synergistic MNs, probably arising from the activation of group III and IV afferents. The effects could in part be due to increased presynaptic inhibition, while recurrent inhibition plays a minor role (Kalezic et al. 2004).

3.2.3.3. Heteronymous Group Ib Afferent Inhibition

Heteronymous inhibition between lower limb muscles is primarily attributed to recurrent inhibitory circuits in humans but could also arise from Golgi tendon organs (GTOs). To distinguish, in humans, between recurrent inhibition and mechanical activation of GTOs, the unique influence of mechanically activated GTOs was examined by comparing the magnitude of heteronymous inhibition from quadriceps (Q) muscle stimulation onto ongoing soleus EMG at five Q stimulation intensities (1.5-2.5× motor threshold) before and after an acute bout of stimulation-induced Q fatigue. Fatigue was used to decrease Q stimulation evoked force (i.e., decreased GTO activation) despite using the same pre-fatigue stimulation currents (i.e., same antidromic recurrent inhibition input). Thus, a decrease in heteronymous inhibition after Q fatigue and a linear relation between stimulation-evoked torque and inhibition both before and after fatigue would support mechanical activation of GTOs as a cause of inhibition. A reduction in evoked torque but no change in inhibition would support recurrent inhibition. After fatigue, Q stimulation-evoked knee torque, heteronymous inhibition magnitude and inhibition duration were significantly decreased for all stimulation intensities. In addition, heteronymous inhibition magnitude was linearly related to twitch-evoked knee torque before and after fatigue. Hence, mechanical activation of GTOs may be a cause of heteronymous inhibition along with recurrent inhibition (Cuadra et al. 2024).

3.2.3.4. Recurrent Inhibition

Fatigue-activated group III/IV afferents might exert their inhibitory effects on MNs via Renshaw cells mediating recurrent inhibition (Figure 2), as suggested by Hayward et al (1991) who felt that this pathway might be involved in specifically regulating MN discharge rate. But at least in cats, Renshaw cells were suppressed by metabolically activated group III/IV afferents (Windhorst et al. 1997).

In cats, by recording changes in Renshaw cell spontaneous discharges and responses to antidromic electrical stimulation of motor axons when small-diameter calf muscle afferents were excited by intra-arterially injected bradykinin, 5-HT, lactic acid and KCI. Whenever such injections had an effect, it transiently raised or lowered the spontaneous firing rate and almost always decreased the antidromic response to motor axon stimulation. This suggests that the Renshaw cell-mediated effects of neurochemically excited afferents would predominantly disinhibit rather than inhibit MNs (Windhorst et al. 1997).

This was consistent with results from another experiment in cats. Using the approach described in Sect., the potential involvement of recurrent inhibition in fatigue conditions was tested by conditioning the monosynaptic H-reflex by stimulation of a filament of VR L7. The intensity of recurrent inhibition first diminished and then gradually recovered after GS fatigue. Recurrent inhibition was slightly decreased but probably plays a minor role (Kalezic et al. 2004).

By contrast, in humans, different results were obtained by recording changes in recurrent inhibition of soleus MNs when high-threshold, group III/IV fibers from the same muscle were tonically activated. At rest, such stimulation produced transient facilitation of both test H and reference H-reflexes. Under weak voluntary contraction, muscle group III/IV fiber stimulation produced long-lasting extra-inhibition and extra-facilitation of the test reflex and reference reflex respectively, the time course of which closely resembled that of the subjective muscle pain curve. It was concluded that the filtering property of recurrent inhibition may contribute to limit MN activity during muscle pain and/or adapt MN firing rate to the modified contractile properties of MUs as muscle fatigue developed (Rossi et al. 2003). This is more in line with the suggestion of Hayward et al (1991).

Comments. The lumped recurrent network depicted in Figure 2 is much simplified because Renshaw cells receive excitatory inputs not only from homonymous and synergistic MNs but also from antagonist MNs and `antagonist’ Renshaw cells mutually inhibit each other. Furthermore, Renshaw cell activity is modulated by sensory inputs and pathways descending from supraspinal sources (Katz and Pierrot-Deseilligny 1999; Windhorst 2021), which may explain the differences between cat and human results.

3.2.3.5. Reciprocal Inhibition

The effects of muscle fatigue on reciprocal Ia inhibition have not been intensively investigated. Here are two examples.

Ten healthy subjects performed intermittent isometric voluntary contraction of the ankle plantarflexion at 50% MVC as the fatiguing task. Reciprocal Ia inhibition was evaluated by the degree of H-reflex amplitude depression in the soleus muscle by the test stimulus following conditioning stimulus to the common peroneal nerve. The difference in H-reflex amplitude between before and after fatiguing task was also checked. There was no significant difference in the degree of H-reflex amplitude depression, although the H-reflex amplitude significantly decreased after the fatiguing task (p < 0.01).This has been interpreted to show that the decrease in H-reflex amplitude was caused by descending inhibitory input from supraspinal sources to MNs, while the excitability of the Ia inhibitory interneuron was not involved (Tanino et al.2004).

Reciprocal Ia inhibition from ankle flexors to extensors was investigated in 12 healthy subjects. The H-reflex in the soleus muscle was used to monitor changes in the amount of reciprocal Ia inhibition from common peroneal nerve as demonstrated during voluntary dorsi- or plantar-flexion and 50 Hz electrical stimulation induced dorsi- or plantar-flexion. The test soleus H-reflex was kept at 20-25% of maximum directly evoked motor response (M response) and the strength of the conditioning common peroneal nerve stimulation was kept at 1.0 x motor threshold. At rest, weak la inhibition was demonstrated in 12 subjects, maximal inhibition from the common peroneal nerve was 28.8%. During voluntary dorsiflexion and 50 Hz electrical stimulation induced dorsiflexion, the absolute amounts of inhibition increased as compared to at rest, and decreased or disappeared during voluntary plantar-flexion and 50 Hz electrical stimulation induced plantar-flexion as compared to at rest. During voluntary or electrical stimulation induced agonist muscle fatigue, the inhibition of the soleus H-reflex from the common peroneal nerve was greater during voluntary dorsi-flexion (maximal, 11.1%) and 50 Hz (maximal, 6.7%) electrical stimulation induced dorsi-flexion than at rest. The inhibition was decreased or disappeared during voluntary plantar-flexion 50 Hz electrical stimulation induced plantar-flexion. These results were considered to support the hypothesis that MNs and la inhibitory interneurons link to antagonist MNs in reciprocal inhibition (Sato et al. 1999).

Comments. If, as for simplicity depicted in Figure 2, only calf muscles were fatigued, selective effects from activated calf group III/IV afferents on reciprocal Ia inhibitory interneurons to antagonist MNs might be of little importance. But whether group III/IV afferents are so selective is by no means clear, calf afferents could also impact the antagonist-related reciprocal Ia interneurons. Furthermore, reciprocal Ia interneurons are inhibited by Renshaw cells (Figure 2). The matter becomes even more complicated by mutual inhibition between reciprocal Ia interneurons (not shown) and when antagonist muscles are active, e.g., during safety stance on a slippery surface. Finally, they receive modulatory inputs from sensory afferents (e.g., disynaptic inhibition from antagonist group Ia afferents, and excitatory and inhibitory effects from cutaneous, joint and groups II, III and IV muscle afferents), from propriospinal neurons, as well as from descending tracts [e.g., CST, VST, RST, ReST]. These influences may also be exerted indirectly via fusimotor neurons (Jankowska 1992; Schomburg 1990). The descending influences will become important below.

3.3. Supraspinal Muscle Fatigue in Health

Neuromuscular fatigue impairs exercise performance through central and peripheral mechanisms. Interactions between the two components can occur via feedback and feedforward processes. Feedback mechanisms, group III/IV afferents link limb muscles with the CNS. As to central mechanisms, corollary discharges copy the neural drive from the motor system to the working muscles and to sensory systems, which might influence fatigue. There is evidence for a previously proposed hypothesis based on the idea that a negative feedback loop operates to protect the exercising limb muscles from severe threats to homeostasis during whole-body exercise. The `sensory tolerance limit’ can be viewed as a negative feedback loop which accounts for the sum of all feedback (locomotor muscles, respiratory muscles, organs, and muscles not directly involved in exercise) and feedforward signals processed within the CNS with the purpose of regulating the intensity of exercise to ensure that voluntary activity remains tolerable (Hureau et al. 2018).

The following discussion will ascend from the spinal cord to the cerebral cortex.

3.3.1. Fatigue-Induced Effects in Supraspinal Structures

Nociceptive and other signals carried by group III/IV afferents are conveyed to supraspinal structures via several distributed ascending tracts. The main spinally ascending pathway is the spino-thalamic tract (STT), which projects to the posterior, medial and lateral thalamus, different nuclei of which project on to different cortical areas from the somatosensory cortices anteriorly to insular and cingulate cortices. STT collaterals target brainstem areas such as various nuclei in the reticular formation (RF), parabrachial nucleus (PBN), peri-aqueductal gray (PAG), hypothalamus and amygdala (Kuner and Kuner 2021).

In anaesthetized rats, muscle fatigue induced by intermittent high-rate electrical stimulation of dorsal neck muscles (mm. trapezius and splenius) produced significant increases in c-fos expression and NADPH-diaphorase reactivity ipsilaterally in the C1-C4 spinal segments as well as in ventro-lateral PAG, the contralateral central (Ce) and medial (Me) nuclei of the amygdala, and the paraventricular nucleus of hypothalamus. Hence, the PAG, limbic structures and the hypothalamus are involved in activation after neck muscle fatigue and might contribute to nociceptive processing and generation of the autonomic and affective components of muscle pain (Vlasenko et al. 1994).

3.3.1.1. Medulla Oblongata

Group III/IV afferents contact DH neurons, which transmit nociceptive, fatigue-related and other signals upwards. Some targets lie in the medulla oblongata.

In anesthetized rats, Fos-i and NADPH-d-positive neurons in the medulla were studied after fatiguing stimulation of hindlimb muscles. After both direct muscle stimulation and L5 VR stimulation, fatigue-related c-fos gene expression was most prominent within the ipsilateral nucleus tractus solitarii (NTS), the caudal ventro-lateral and rostral ventro-lateral reticular nuclei, and the intermediate reticular nucleus. Fos-ir neurons were co-distributed with NADPH-d-reactive cells within the dorso-medial medulla (DMM) and ventro-lateral medulla (VLM), and double-staining neurons were found in the NTS, intermediate reticular nucleus and lateral paragigantocellular nucleus (Maisky et al. 2002).

In response to fatiguing contractions of the triceps-surae muscles in cats, immune-reactive neurokinins were released in the lateral reticular nucleus, ventral regions of the NTS and the medial vestibular nucleus, suggesting that tachykinin neurons may be a component of the pathways regulating blood pressure during ergoreceptor activation (Williams et al. 1995). In response to fatiguing isometric contractions, immunoreactive substance P-like substances (irSP) were released from sites in the medial NTS (mNTS) and interacted with NK-1 receptors in the area to affect the cardio-vascular responses during the muscle pressor reflex (Williams and Fowler 1997).

3.3.1.2. Peri-Aqueductal Gray (PAG)

The PAG is a cell-dense region surrounding the midbrain aqueduct. It shows a high degree of anatomical and functional organization, which takes the form of longitudinal columns of afferent inputs, output neurons and intrinsic interneurons (Bandler and Shipley 1994; Koutsikou et al. 2017). The PAG receives ascending sensory inputs from nociceptive and thermo-sensitive fibers of the STT, the nociceptive inputs being relayed by the PBN (Kuner and Kuner 2021). The ventro-lateral (vlPAG) column receives direct input from the spinal DH and evokes an opioid-mediated analgesia together with a distinct set of coping behaviors including quiescence. Conversely, the lateral PAG (lPAG) receives direct inputs from the DH and SpV. This organization is consistent with the behavioral response when activated with rostral lPAG stimulation evoking forward defense and caudal lPAG stimulation evoking a fleeing response (Mills et al. 2021). The lPAG and dorso-lateral PAG (dlPAG) are involved in defense reactions associated with tachycardia, hypertension, and re-distribution of bloodflow by activation of sympathetic preganglionic fibers to relevant effectors. By contrast, the ventro-lateral column inhibits sympatho-excitatory neurons of the RVLM and activate the pre-ganglionic vagal neurons, thus initiating passive coping responses with immobility, bradycardia and hypotension. Active coping associated with sympatho-excitation goes along with opioid-independent analgesia and increased motor activity (locomotion), while passive coping associated with sympatho-inhibition concurs with opioid-mediated analgesia and motor freezing (Lamotte et al. 2021).

This raises the question whether muscle fatigue could also affect the PAG. Indirect signs exist. In response to fatiguing isometric contractions of the hind-limb muscles in cats, immunoreactive enkephalins were released. During fatiguing contractions, mean arterial blood pressure increased by 76 +/- 9 mmHg above resting and recovery levels. Levels of immuno-reactive enkephalins were elevated in the dlPAG during the isometric contraction when compared to resting levels. It is possible that isometric muscle contraction causes the release of Met-enkephalin-like substances in the PAG (Williams et al. 1992).

3.3.1.3. Amygdala

The amygdala is comprised of different nuclei; the lateral amygdala (LA), baso-lateral (BLA), medial (MeA), baso-medial (BMA) and central (CeA) nuclei and in between, the intercalated cells. The CeA receives direct and indirect nociceptive inputs from the STT and from the PBN (Allen et al. 2021; Kuner and Kuner 2021), and from several other regions. CeA output targets the PAG and the rostral ventro-medial medulla (RVMM), which are critical for mediating behavioral coping responses in the face of threat. Descending modulation of spinal nociceptive processing by CeA-PAG connections has been implicated in anti-nociceptive effects of opioids acting locally in the BLA (Kuner and Kuner 2021).

In anesthetized rats, c-fos gene expression in the cervical spinal cord and amygdala was examined after muscle fatigue caused by intermittent high-rate electrical stimulation of the dorsal neck muscles (m. trapezius and m. splenius). Fatigue-related increases in c-fos expression occurred on the stimulated muscle side in spinal segments C2-C4 (layers 1, 3-5, 7 and 10), bilaterally in the lumbar L4-L6 (layer 1) segments and in contralateral CeA, MeA, and BMA amygdaloid nuclei. A scarce number of staining cells were found within LA and BLA nuclei. The rostro-caudal extent of c-fos expression in the spinal cord supports functional coupling of the cervical and lumbar regions during neck-muscle fatigue development. The distinct c-fos expression in the CeA and MeA nuclei suggests that they may contribute to mediating the neck muscle fatigue-related nociception, autonomic and behavioral responses (Maznychenko et al. 2007).

3.3.1.4. Blood-Pressure and Respiratory Control in Medulla and Amygdala

It has been proposed that cardio-vascular and ventilatory responses to exercise are regulated by (i) a feedforward `central command’ and (ii) a feedback signal from contracting muscles (Amann 2012). Somatosensory feedback, specifically from group III and IV muscle afferents, influences cardio-ventilatory responses to leg rhythmic exercise in humans. Lumbar intrathecal fentanyl injections were used to impair the central projection of spinal opioid receptor-sensitive muscle afferents. With a number of controls, this approach allowed to demonstrate the essential contribution of group III and IV muscle afferent feedback to the cardio-vascular, ventilatory and perceptual responses to rhythmic exercise in humans, even in the presence of unaltered contributions from other major inputs to cardio-ventilatory control (Amann et al. 2010).

Cardio-vascular Regulation. In cats subjected to isometric exercise to fatigue, ergoreceptor signals may be processed through the PAG and the VLM to control arterial blood pressure (Williams et al. 1990). The rostral VLM contains premotor sympatho-excitatory neurons, which are involved in reflex control of blood pressure and responses to internal stressors. The caudal VLM plays a critical role in cardio-vascular regulation and relays reflex influences to medullary and hypothalamic effectors (Benarroch 2020; Sved et al. 2000). The nucleus paragigantocellularis in the VLM has been implicated in cardio-vascular, nociceptive and analgesic functions. It receives afferents from most laminae of the spinal cord, the caudo-lateral medulla, the medial reticular nuclei of the medulla and pons, the contralateral nucleus paragigantocellularis, the NTS, the medial vestibular nucleus, and issues major projections to the pontine LC (Andrezik et al. 1981; van Bockstaele et al. 1989).

Cardio-vascular regulation during high-intensity exercise has been hypothesized implicate the amygdala whose activation acts to limit maximum exercise performance. In Wistar rats subjected to maximum exercise, total running time and cardio-vascular responses were compared before and after bilateral CeA lesions, activated neurons were recorded in CeA and/or the hypothalamic paraventricular nucleus (PVN) that project to the nucleus tractus solitarii (NTS). (i) CeA lesions resulted in an increase in the total exercise time and the time at which an abrupt increase in arterial pressure appeared, indicating an apparent suppression of fatigue. (ii) High-intensity exercise activated both the PVN-NTS and CeA-NTS pathways. (iii) These suggests that cardio-vascular responses during high-intensity exercise are affected by CeA activation, which acts to limit maximum exercise performance, and may implicate autonomic control modulating the PVN-NTS pathway via the CeA (Tsukioka et al. 2022).

Respiration. The mammalian medulla oblongata contains a network (central pattern generator) that generates the rhythmic respiratory activity, with the core circuitry residing in the VLM and a small nucleus in the pons. This network receives external inputs from pulmonary and chemo-receptive afferents, which elicit a number of respiratory reflexes which regulate ventilation and protect the airways (Lalley 2009; McCrimmon and Alheid 2009, Richter and Smith 2014).

This activity must be able to adapt to various conditions, particularly physical exercise. Evidence indicates that group III/IV muscle afferents indirectly affect locomotor performance by influencing neuromuscular fatigue. These neurons regulate the hemodynamic and ventilatory responses to exercise and, thus, assure appropriate locomotor muscle O₂ delivery, which optimizes peripheral fatigue development and facilitates endurance performance (Amann et al. 2020).

3.3.1.5. Hypothalamus

The hypothalamus is a diencephalic structure in the basal forebrain, consisting of several nuclei that are critical for integrated autonomic and neuro-endocrine responses for homeostasis and adaptation to internal or external stimuli (Takayanagi and Onaka 2021). The hypothalamus receives converging nociceptive and visceral inputs from the spinal and trigeminal DHs, and direct and indirect (via PBN and NA A1 cells) nociceptive inputs from the STT (Kuner and Kuner 2021).

Ill-planned intense and exhaustive exercise may have deleterious effects. The effects of a short-duration exhaustive exercise on body chemical composition and hypothalamic-pituitary-adrenal (HPA) axis was investigated in C57Bl/6 mice. Exhaustive exercise consisted of a daily running session at 85 % of maximum speed until the animal reached exhaustion. Body weight as well as total body water, fat and protein content were determined from animal carcasses. HPA activation was assessed by plasma corticosterone levels measured by radioimmunoassay and the weight of both the adrenal glands and thymus were measured. Plasma corticosterone levels increased by 64%. The weight of the adrenal glands augmented by 74% and 45%, at 4 and 10 days of IE, respectively. The total carcass fat content decreased by 20% only at 4 days exhaustive exercise, whereas protein content decreased by 20%. Exhaustive exercise may be related to HPA-axis activation associated with remodeling of body chemical composition in C57BL/6 mice (Rosa et al. 2014).

3.3.1.6. Cerebellum

The cerebellum has been implicated in a number of functions, including oculomotor control, control of upright stance and locomotion, reaching and grasping and speech, timing and coordination of movement, control of motor-cortex excitability, prediction of sensory consequences of actions, error detection and correction, motor learning, classical conditioning (e.g. eyeblink conditioning), and even reward, language, and social behavior, emotional, motivational and cognitive functions. The cerebellum also has a role in pain processing and/or modulation, possibly due to its extensive connections with the prefrontal cortex (PFC) and brainstem regions involved in descending pain control (Adamaszek et al. 2017; Wang et al. 2022).

Nociceptive signals reach the cerebellum, among other structures (below),, and thus fatigue-related signals could also do so.

Alterations in sensory input due to neck muscle fatigue impact upper-limb sensory-motor processing, suggesting that neck fatigue may also impact cerebellum-to-motor cortex pathways in response to motor learning. Normally motor learning decreases cerebellar inhibition (CBI) to facilitate learning of a novel skill. Cervical extensor-muscle fatigue altered cerebellar inhibition in response to motor learning in that neck fatigue before motor skill acquisition led to less decrease in cerebellar inhibition and significantly less improvement in performance accuracy compared to a control group. Neck fatigue impacted the cerebellar-motor cortex interaction to distal hand muscles (Zabihhosseinianet al. 2020).

3.3.1.7. Cerebral Cortex

Group III/IV input reaches the cerebral cortex and has been suggested to inhibit descending drive to MNs by depressing motor-cortex (M1) excitability (Amann 2012; Amann et al. 2020). Another interpretation suggests that this inhibitory effect is counterbalanced by a motivational input that facilitates M1 output in order to overcome supraspinal fatigue (Tanaka and Watanace 2012).

Brain imaging and transcranial stimulation have been used to determine changes in brain areas after fatiguing muscle contractions of various sorts. Results have been somewhat variable.

Functional Magnetic Resonance Imaging (fMRI). Twelve healthy human subjects performed a submaximal (30%) intermittent fatiguing handgrip exercise (3 s grip, 2 s release, left hand) for approximately 9 min during fMRI scanning. Regression analysis was used to measure changes in fMRI signal from primary sensory-motor cortex (S1), premotor cortex (PM) and visual cortex (V1) in both hemispheres. Muscle force declined compared to pre-fatigue maximal force. The fMRI signal from S1 contralateral to the fatiguing hand increased compared to baseline. The fMRI signal from the ipsilateral S1 did not change significantly. The signal from V1 increased significantly for both hemispheres compared to baseline. This is in keeping with the notion of an increase in sensory processing and corticomotor drive during fatiguing exercise to maintain task performance as fatigue develops (Benwell et al. 2007).

Using fMRI in humans performing index-finger abduction tasks, several motor areas in the brain showed increased activity with increased muscle activity, both during force modulation and motor fatigue. The cerebellum showed a smaller increase in activation during compensatory activation due to fatigue, while additional activation was found in the pre-supplementary motor area and in a frontal area. During motor fatigue, force production decreased, force variability increased, and muscle activity increased. Brain areas comparable with the aforementioned areas also showed stronger activation over time. During fatigue, the subjects’ MVC force was reduced, accompanied by a decrease in activation of the supplementary motor area (sma). This suggests that especially the activity in the sma and frontal areas is affected by motor fatigue (van Duinen et al. 2007).

Human subjects showed differences in fMRI-measured cortical neuronal activation before and after different long-lasting contractions: right-hand movements with minimum, maximum, and post-fatigue maximum finger flexion. As compared to maximum movement, the total number of active voxels in primary sensory-motor (S1) areas, sma and cerebellum was strongly reduced in post-fatigue maximum movement (Storti et al. 2014).

Motor Cortex Stimulation. Single-pulse TMS in humans revealed a reduction in motor-cortex excitability when measured in relaxed muscle following sustained fatiguing contractions. The reduction occurred in motor-evoked potentials. During maximal and sub-maximal fatiguing contractions, voluntary activation measured by TMS decreased, suggesting the presence of supraspinal fatigue. This does not eliminate the possibility of spinal contributions. Comparing EMG responses to paired-pulse stimuli at the cortical and sub-cortical levels suggested that impaired MN responsiveness rather than intra-cortical inhibition may contribute to the development of central fatigue (Gruet et al. 2013).

There is evidence that the cortical inhibition is mediated by intra-cortical interneuron activity, which may contribute to central fatigue, and that spinal opioid receptor-sensitive muscle afferents might influence central fatigue by facilitating intra-cortical inhibition (Hilty et al. 2011). Indeed, feedback from group III/IV muscle afferents innervating locomotor muscles diminished the excitability of the motor cortex during fatiguing cycling exercise. This result is, at least in part, from the facilitating effect of these afferents on inhibitory GABA_B intra-cortical interneurons (Sidhu et al. 2018).

In humans, whole body exercise (e.g., such as cycling or rowing) did not alter the net excitability of the cortico-spinal pathway during fatigue. This lack of an apparent effect does not mean that changes do not occur, but that there may be a counterbalance of excitatory and inhibitory influences on the two components of the cortico-spinal pathway, namely the motor cortex and the spinal MNs (Weavil and Amann 2018).

3.3.1.8. Cortico-Cerebello-Basal Ganglia-Thalamic System

The cerebral cortex, BG, cerebellum and thalamus are intimately related by being reciprocally connected with each other (Figure 3). It thus appears that the cortex works in concert with the thalamus, cerebellum and BG, constituting an integrated cerebello-BG-thalamo-cortical system and working in learning and control processes (Caligiori et al. 2017). The neocortex itself communicates bidirectionally and in simple and complex ways with the thalamus, forming cortico-thalamo-cortical loops, tightly interlinked with local cortical and cortico-cortical circuits and involving (massive) excitatory and inhibitory connections. The cerebellum and BG participate in multi-regional loops via their connections with the cortex and thalamus (Shepherd and Yamawaki 2021; Figure 3).

Two pathological examples may serve as support for the network operation.

Dystonia is a brain disorder characterized by sustained involuntary muscle contractions. It is typically inherited as an autosomal dominant trait with incomplete penetrance. Primary dystonia is considered to involve micro-structural and functional changes in neuronal circuitry (Argyelan et al. 2009). Dystonia is a good example of how abnormal activity in the cerebellum may propagate to the BG and cause dysfunction. In many forms of dystonia, abnormalities occur in the cerebello–thalamo–cortical pathways, cerebellar activity and functional connectivity. For example, as compared to controls, manifesting and non-manifesting carriers of genetic mutations that are associated with dystonia showed co-varying increases in metabolic activity in the putamen–GP and in the cerebellar cortex. Mouse models of dystonia also displayed structural and functional abnormalities in cerebello-thalamo-cortical pathways. In such models, abnormal (for example, bursting) cerebellar output evoked dystonic postures. Silencing, lesioning or normalizing cerebellar output abolished the dystonic postures. In keeping with these data, bursting cerebellar output has been recorded during surgery in a patient with dystonia (Bostan and Strick 2018). Magnetic resonance diffusion tensor imaging showed reduced integrity of cerebello-thalamo-cortical fiber tracts. In these subjects, reductions in cerebello-thalamic connectivity correlated with increased motor activation responses, consistent with loss of inhibition at the cortical level (Argyelan et al. 2009).

Figure 3. Simplified block diagram of the cortico-cerebello-basal ganglia-thalamic system. The intricate circuitries within the cerebral cortex, BG, cerebellum and thalamus are omitted for simplicity. The cerebral cortex and thalamus interact in complex ways, involving the cerebral and thalamic networks with excitatory and inhibitory connections, where the purple double-arrowed lines symbolize excitatory projections which, however, most often also exert inhibitory actions by GABA interneurons in the target structure. The cortico-BG connection (the striatum being the BG input station) is direct and excitatory. The cortico-cerebellar connection is mediated via the pontine nuclei (PN). At least in part, the BG-to-cerebellum connection also runs through the PN, while the inverse cerebellum-to-BG connection travels via the thalamus. The pathways from BG and cerebellum to the cerebral cortex involve the thalamus. The red line symbolizes inhibitory effects exerted by the BG output station, the GPi/SNr. Green arrowed lines symbolize excitatory connections. Abbreviations: CL, centro-lateral nucleus; CM: centro-median nucleus; DCN: deep cerebellar nuclei; GPi: globus pallidus internus; PN: pontine nuclei; SNr: substantia nigra pars reticularis; STN: subthalamic nucleus; VA: ventro-anterior nucleus; Vim: ventro-intermediate nucleus; VL: ventro-lateral nucleus. Data from Bostan and Strick (2018); Shepherd and Yamawaki (2021); Wichmann and DeLong (2016).

Figure 3. Simplified block diagram of the cortico-cerebello-basal ganglia-thalamic system. The intricate circuitries within the cerebral cortex, BG, cerebellum and thalamus are omitted for simplicity. The cerebral cortex and thalamus interact in complex ways, involving the cerebral and thalamic networks with excitatory and inhibitory connections, where the purple double-arrowed lines symbolize excitatory projections which, however, most often also exert inhibitory actions by GABA interneurons in the target structure. The cortico-BG connection (the striatum being the BG input station) is direct and excitatory. The cortico-cerebellar connection is mediated via the pontine nuclei (PN). At least in part, the BG-to-cerebellum connection also runs through the PN, while the inverse cerebellum-to-BG connection travels via the thalamus. The pathways from BG and cerebellum to the cerebral cortex involve the thalamus. The red line symbolizes inhibitory effects exerted by the BG output station, the GPi/SNr. Green arrowed lines symbolize excitatory connections. Abbreviations: CL, centro-lateral nucleus; CM: centro-median nucleus; DCN: deep cerebellar nuclei; GPi: globus pallidus internus; PN: pontine nuclei; SNr: substantia nigra pars reticularis; STN: subthalamic nucleus; VA: ventro-anterior nucleus; Vim: ventro-intermediate nucleus; VL: ventro-lateral nucleus. Data from Bostan and Strick (2018); Shepherd and Yamawaki (2021); Wichmann and DeLong (2016).

Tourette Syndrome (TS) and Obsessive–compulsive Disorder (OCD). Although the precise origin of tics in TS patients is still unclear, reduced GABA function in the striatum may be a primary cause of tic production. Microinjections of the GABA antagonist bicuculline into the striatum or into the globus pallidus externus of non-human primates can result in tics and stereotyped behaviors. Moreover, abnormal BG activity drives activity changes in both the cerebellum and the primary motor cortex (M1) that predict the onset of tics. Imaging studies in humans provided additional evidence for cerebellar involvement in TS, which revealed tic-related activation not only in the BG but also in the cerebellum. Brain imaging of both TS and OCD patients revealed changes in cerebellar activity. For example, relative to healthy controls, resting-state fMRI demonstrated that individuals with OCD exhibited increased whole-brain connectivity in regions of both the putamen and the cerebellar cortex. Also, in individuals with TS, brain metabolism was characterized by hypometabolism in the striatum co-varying with hypermetabolism in the cerebellar cortex. It has been proposed that the disynaptic pathway from the STN to the cerebellar cortex (Figure 3) may provide a link for such effects, although other pathways or independent structural changes in the cerebellum may also be involved. A recent computational model of BG–cerebellar–cerebral cortical network function in TS indicated that hyperactivity in the STN may propagate to the cerebellar cortex and contribute to tic generation (Bostan and Strick 2018).

Healthy Human Volunteers. Alterations of cerebral activity during prolonged static force exertion was determined by regional cerebral blood flow (rCBF) using H2(15)O positron emission tomography (PET) while six male healthy subjects pressed a morse-key with their right index finger with a constant force of 20% of MVC for different periods of time (1.5-4.5 min). Despite a considerable sense of fatigue and increased effort at the end of a 4.5 min. key press, no compensatory changes of activity were detected in motor or sensory related structures. In the right dorso-lateral PFC, the rCBF was significantly correlated with the duration of key-press, possibly reflecting processes overriding fatigue. In this static force task, the basal ganglia (BG) were strongly activated, but not in a previous force task involving repetitive dynamic force pulses, suggesting that sustained exertion of a static force is an active process modulated, at least in part, by the BG (Dettmers et al. 1996).

Healthy human volunteers performed a sustained handgrip contraction for 225 s and 320 intermittent handgrip contractions (approximately 960 s) at 30% maximal level, while fMRI was used to image their brain. For the sustained contraction, EMG signals of the finger flexor muscles increased linearly while the target force was maintained. The fMRI-measured cortical activities in the contralateral sensory-motor cortex increased sharply during the first 150 s, then plateaued during the last 75 s. For the intermittent contractions, the EMG signals increased during the first 660 s and then began to decline, while the handgrip force also showed a sign of decrease despite maximal effort to maintain the force. The fMRI signal of the contralateral sensory-motor area showed a linear rise for most part of the task and plateaued at the end. For both tasks, the fMRI signals in the ipsilateral sensory-motor cortex, PFC, cingulate gyrus, sma, and cerebellum exhibited steady increases. The brain thus increased its output to reinforce the muscle for the continuation of the performance and possibly to process additional sensory information (Liu et al. 2003). These results are somewhat at variance with those reported by Dettmers et al. (1996).

Healthy human subjects executed simple motor tasks before and under motor fatigue. fMRI showed that in both conditions, movements activated sensory-motor areas, sma, cerebellum, thalamus and BG. Importantly, the intensity and size of activation volumes in the sub-cortical areas, including thalamus and BG areas, were significantly decreased during motor fatigue, implying that fatigue disturbs the motor-control processing in a way that both sensory-motor areas and sub-cortical brain areas are less active (Hou et al. 2016).

Functional Connectivity in Muscle Fatigue. During muscle fatigue induced by intermittent handgrips at 50% of their MVC level, functional connectivity between fMRI signals of the M1 and the BG, cerebellum, and thalamus were determined. Widespread, statistically significant increases in functional connectivity occurred in bilateral BG, cerebellum, and thalamus with the left M1 during significant versus minimal fatigue stages. These sub-cortical nuclei are critical components in the motor control network and actively involved in modulating voluntary muscle fatigue, possibly, by working together with the M1 to strengthen the descending central command to prolong the motor performance (Jiang et al. 2016).

3.3.2. A Long Way Down: From Cerebral Cortex to Spinal Cord

3.3.2.1. Insufficient Drive from Motor Cortex

Even maximal voluntary effort to contract a muscle or group of muscles activates human MNs and muscle fibers only sub-optimally, maximal voluntary strength thus often being below true maximal muscle force. This could be demonstrated by TMS over the motor cortex. For example, when stimulus intensity is set appropriately, TMS during an isometric MVC of the elbow flexors commonly evoked a small twitch-like increment in flexion force, indicating that, despite the subject’s maximal effort, motor cortical output at the moment of stimulation was not maximal and was not sufficient to drive the MNs to produce maximal force from the muscle. TMS has uncovered focal changes in cortical excitability and inhibitability based on EMG recordings, and a decline in supraspinal `drive’ based on force recordings. The mechanisms of supraspinal fatigue are unclear. Although changes in the behavior of cortical neurons and spinal MNs occur during fatigue, they can be dissociated from supraspinal fatigue. Furthermore, in whole-body endurance performance, the brain monoaminergic neurotransmitter systems play a role, particularly with regard to exercise in hot environments (below) (Gandevia 2001; Taylor et al. 2016).

However, things are a bit more complicated. The properties of the cortico-spinal pathways change during fatiguing exercise in ways that could influence the development of central fatigue. Based on differences in motor cortical and MN excitability between exercise modalities (e.g. single-joint vs. locomotor exercise), the effect of these changes on functional impairments and performance limitations are not clear. There is though strong evidence for marked `inhibition’ of MNs as a direct result of voluntary drive (Amann et al. 2022).

The interaction between the cerebral cortex and the spinal cord also involves, besides `purely’ motor pathways, neuromodulatory systems, including monoaminergic ones.

3.3.2.2. Substantia Nigra Pars Compacta and Dopamine (DA)

In rodents, exercise increases the release of several neurotransmitters in different brain regions and the onset of fatigue can be manipulated when DA influx in the preoptic and anterior hypothalamus is increased, interfering with thermoregulation. In humans, things are not as straightforward: most studies manipulating brain neurotransmission failed to change the onset of fatigue in normal ambient temperatures. When the ambient temperature was increased, DA and combined DA and NA reuptake inhibition appeared to override a safety switch, allowing subjects to push harder and become much warmer, without changing their perception. In general, brain neurochemistry is clearly involved in the complex regulation of fatigue, but many other mediators also play a role (Meeusen and Roelands 2018). Adaptations in the DA systems may influence exercise capacity. For example, a reduction in DA neurotransmission in the substantia nigra pars compacta (SNpc) could impair activation of the BG and reduce stimulation of the motor cortex leading to central fatigue. Habitual wheel running produced changes in DA systems. Six weeks of wheel running sufficed to increase tyrosine hydroxylase mRNA expression and reduce D2 auto-receptor mRNA in the SNpc. The same exercise increased D2 postsynaptic receptor mRNA in the caudate putamen, a major projection site of the SNpc (Foley and Fleshner 2008).

3.3.2.3. Raphé Nuclei and Serotonin (5-HT)

The raphé nuclei and ventral tegmental filed (VTA) are a collection of functionally and anatomically diverse cell groups that span the brainstem and contain the majority of the 5-HT-producing neurons in the CNS (Brodal 1981). Noxious peripheral stimuli cause activity changes in neurons of the RVMM, which contains the nucleus raphé dorsalis (NRD). Raphé neurons are sensitive to fatigue, but differentially.

In adult male cats, single-unit activity of presumed 5-HT neurons in the mesencephalon (NRD) or medulla oblongata [nucleus raphé obscurus (NRO) and nucleus raphé pallidus (NRP)] was recorded during prolonged treadmill locomotion. Treadmill speed was set at a moderate level (0.4 m/s) in order to induce long-duration locomotion. The typical time to `fatigue’ (failure to keep pace, falling behind and reluctance to continue) was approximately 40 min in both groups, at which point cats typically displayed marked panting and vocalization. The activity of NRD neurons was unchanged from baseline during the locomotion trial and during the recovery phase. By contrast, the activity of NRO/NRP neurons decreased steadily across the locomotion trial, reaching a mean decrease of approximately 50% (during the first min after the treadmill was turned off). Full recovery of single unit activity to a level approximating the baseline discharge rate required 30-45 min (Fornal et al. 2006).

5-HT Effects on MNs. Endogenous forms of neuromodulation, e.g., by 5-HT, can directly affect MN output and central fatigue (Amann et al. 2022). 5-HT potently regulates neuronal firing rates, which can influence the force that can be generated by muscles during voluntary contractions. MN discharge can be facilitated or suppressed depending on the 5-HT receptor sub-type activated. The release of 5-HT from descending tracts into the spinal cord is linked to the level of motor activity being performed, where 5-HT can increase the discharge rate of MNs via excitatory 5-HT receptors on the soma and dendrites. This in turn can lead to increased voluntary muscle activation and maximal force generation. However, intense or long-lasting release of 5-HT onto MNs may lead to a spillover of 5-HT into extracellular compartments to activate inhibitory 5-HT receptors on the axon initial segment. This can cause a reduction in MNs discharge rate, thus decreasing voluntary muscle activation and maximal force generation. 5-HT may thus have different effects when neuromuscular fatigue induced by contractions of different intensities. Thus, enhanced levels of 5-HT reduced voluntary activation of muscle when fatigue was induced by strong but not weak contractions (Cotel et al. 2013; Henderson et al. 2022; Kavanagh and Taylor 2022).

3.3.2.4. Locus Coeruleus and Noradrenaline (NA)

The LC is a collection of NA cell groups A5 and A6 in the rostral pons of animals and humans. Noxious peripheral stimuli indirectly increase the activity in LC. In anesthetized rats, LC neurons were potently activated by foot shock (Chiang and Aston-Jones 1993). Whether LC receives fatigue-related signals is not clear.

It has been suggested that NA, but not DA re-uptake inhibition, contributes to the development of central/supraspinal fatigue after a prolonged cycling exercise performed in temperate conditions (Klass et al. 2012). Compared with placebo intake, the NA re-uptake inhibitor reboxetine (REB) reduced the endurance time and the MVC torque at task failure. The level of voluntary activation tested by TMS and electrical stimulation decreased at the end of the task. Although the motor-evoked potential did not change during fatigue, the H-reflex and electrically evoked torque decreased similarly in the placebo and REB conditions. After exercise, the reaction time increased in the REB condition but did not change in the placebo condition. This suggested that because of the NA re-uptake inhibition, the output from the motor cortex is decreased at a greater rate than that in the placebo condition, contributing thereby to shorten endurance time (Klass et al. 2016).

It is mentioned in passing that more neurotransmitters (e.g., NO, GABA) can also influence fatigue (Foley and Fleshner 2008).

4. Concluding Remarks

Abbreviations

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