Critical considerations of the contribution of the corticomotoneuronal pathway to central fatigue

Abstract

Neural drive originating in higher brain areas reaches exercising limb muscles through the corticospinal-motoneuronal pathway, which links the motor cortex and spinal motoneurones. The properties of this pathway have frequently been observed to change during fatiguing exercise in ways that could influence the development of central fatigue (i.e. the progressive reduction in voluntary muscle activation). However, based on differences in motor cortical and motoneuronal excitability between exercise modalities (e.g. single-joint vs. locomotor exercise), there is no characteristic response that allows for a categorical conclusion about the effect of these changes on functional impairments and performance limitations. Despite the lack of uniformity in findings during fatigue, there is strong evidence for marked 'inhibition' of motoneurones as a direct result of voluntary drive. Endogenous forms of neuromodulation, such as via serotonin released from neurones, can directly affect motoneuronal output and central fatigue. Exogenous forms of neuromodulation, such as brain stimulation, may achieve a similar effect, although the evidence is weak. Non-invasive transcranial direct current stimulation can cause transient or long-lasting changes in cortical excitability; however, variable results across studies cast doubt on its claimed capacity to enhance performance. Furthermore, with these studies, it is difficult to establish a cause-and-effect relationship between brain responsiveness and exercise performance. This review briefly summarizes changes in the corticomotoneuronal pathway during various types of exercise, and considers the relevance of these changes for the development of central fatigue, as well as the potential of non-invasive brain stimulation to enhance motor cortical excitability, motoneuronal output and, ultimately, exercise performance.

Keywords: central nervous system; motor cortex; muscle fatigue; spinal motoneurones.

Figure 1. Diagrams to show the inputs to the motoneurones (A) and some of the ways by which serotonin may modify motoneuronal output

(B). A: Summary of descending and other inputs to alpha motoneurones for an agonist muscle. Cells with solid circles are inhibitory. Dashed curved regions at premotoneuronal terminals denote presynaptic inhibition acting selectively on the afferent paths to the motoneurone. Inputs to gamma motoneurones are not included. Modified from Gandevia (2001) B: Two schematics to show the potential effects of different levels of voluntary drive on the motoneuronal output as modified by release of serotonin (5-HT) from descending monoaminergic paths. Above: at low levels of voluntary drive, motoneuronal output can be facilitated via 5-HT acting on intrasynaptic receptors in the soma-dendritic region. Below: at higher sustained levels of drive, the local concentration of 5-HT increases to such an extent that it spreads to activate inhibitory receptors at the axon initial segment (AIS) and can thus reduce the firing frequency of the motoneurone.

Figure 2. Reductions in motoneuronal excitability induced by maximal and submaximal isometric exercise.

Raw traces of biceps brachii CMEPs recorded from a single participant during a sustained maximal (McNeil et al., 2009) or submaximal (McNeil et al., 2011) isometric contraction of the elbow flexors. CMEPs are recorded during the SP following TMS (100 ms ISI between TMS and CMS), and the reduction in CMEP size reflects a decrease in motoneuronal excitability because biceps brachii M_max increases during these tasks. Beneath each set of traces is a schematic representation of the biceps brachii motoneurone pool. Circles represent motoneurones of different size, whereas the colour indicates the presumed activation during the fatiguing contraction (black = active throughout, grey = active part of the time, white = not active at any point). The horizontal line above them indicates the motoneurones that would likely contribute to the CMEP considered in each set of traces (i.e., a small CMEP would involve only small, low-threshold motoneurones). Left traces: During a sustained 2-min maximal voluntary contraction (MVC), the reduction in motoneuronal excitability was so rapid that the CMEP was virtually abolished after 16 s. Middle and right traces: After six minutes of a sustained 10-min contraction at the level of integrated EMG activity produced at 25% MVC torque (25% iEMG), there was a marked decrease of the small CMEP (~15% M_max) but a modest decrease of the large CMEP (~50% M_max). This indicates that impairment of motoneuronal excitability is limited to the parts of the pool that have been repetitively activated. For comparable findings in the lower limb see (Finn et al., 2018).

Figure 3. Examples of variability in outcomes reported between exercise performance (time-to-task failure; TTF) and corticomotoneuronal excitability.

Preliminary data from single joint elbow flexion exercise (panels A and B; figures taken from Williams et al., 2013) demonstrating that (A) an increase in exercise performance with anodal tDCS (atDCS) applied during exercise is not accompanied by (B) changes in corticomotoneuronal excitability. In A, dark circles represent participants who received tDCS through to task failure in both conditions (Full-Time; n=8), whereas open circles represent participants for whom tDCS terminated before they reached task failure for one or both stimulation conditions (Part-Time; n=10). In B, MEP amplitude (mean ± SEM) increases to a similar extent from pre-tDCS to 7 min of delivering tDCS measured during the 20% maximum voluntary contraction task in participants who reached task failure before tDCS was discontinued (i.e., Full-Time; n= 8 out of 18). *denotes difference from “Pre-tDCS”; P< 0.05. **denotes main effect of stimulation condition since MEP prior to applying tDCS were significantly lower in Anodal compared to Sham session P < 0.05. Data from cycling study (panel C and panel D, from (Sidhu, 2021)) demonstrating (C) an increase in TTF, but (D) an attenuation in corticomotoneuronal excitability measured via resting MEP in a hand muscle (% M_max; normalized to values post tDCS; mean ± SEM) in the condition when anodal tDCS was applied prior to cycling exercise compared to sham condition at 0 min (P0), 10 min (P10) and 20 min (P20) post cycling exercise. *main effect of session; P < 0.05.