The central drive to the muscle reduces when muscle force wanes during sustained MVC, and this is generally considered the neurophysiological footprint of central fatigue. The question is if force loss and the failure of central drive to the muscle are responsible mechanisms of fatigue induced by un-resisted repetitive movements. In various experimental blocks, we validated a 3D-printed hand-fixation system permitting the execution of finger-tapping and maximal voluntary contractions (MVC). Subsequently, we checked the suitability of the system to test the level of central drive to the muscle and developed an algorithm to test it at the MVC force plateau. Our main results show that the maximum rate of finger-tapping dropped at 30 s, while the excitability of inhibitory M1-intracortical circuits and corticospinal excitability increased (all by approximately 15%). Furthermore, values obtained immediately after finger-tapping showed that MVC force and the level of central drive to the muscle remained unchanged. Our data suggest that force and central drive to the muscle are not determinants of fatigue induced by short-lasting un-resisted repetitive finger movements, even in the presence of increased inhibition of the motor cortex. According to literature, this profile might be different in longer-lasting, more complex and/or resisted repetitive movements.

We tested peripheral, spinal and cortical excitability during 3 minutes of unresisted finger tapping at the maximal possible rate, which induced fatigue. Subsequently, we studied the temporal dynamics of muscle fatigue, expressed in the tapping movement profile, and its relationship to neural systems using mixed model analyses. The tapping rate decreased by 40% over the duration of the task. The change in the amplitude of the range of motion was not significant. The excitability of the flexor and extensor muscles of the index finger was tested via evoked potentials obtained with various types of stimulation at various levels of the motor system. the change in spinal excitability with time was evaluated considering the simultaneous changes in muscle excitability; we also considered how spinal excitability changed over time to evaluate cortical excitability. Excitability in the flexor and extensor muscles at the different levels tested changed significantly, but similar excitability levels were observed at notably different tapping rates. Our results showed that only 33% of the decrease in the tapping rate was explained by changes in the excitability of the structures tested in the present work.Determining the central mechanisms involved in muscle fatigue is important from a physiological perspective and can also have relevant implications from an applied perspective when we refer to sports, ergonomics or certain pathological conditions. These mechanisms have been studied thoroughly in the case of isometric muscle contractions; they include changes in excitability both at the spinal cord and M1 networks 1-8 .Another type of muscle activity corresponding to the contractions performed during rhythmic repetitive movements (RRMs) is essential in daily living and may result in fatigue. Traditionally, their central expressions of fatigue have been studied at the point at which an activity has been completed 9,10 , which is a limitation because the CNS recovers very quickly when the activity ends 11,12 . Several works recently tested fatigue at the central level immediately following the end of unresisted RRMs without allowing time for CNS recovery 5,13,14 . The reduction in the maximal movement rate was greater after 30 s of finger tapping (ft) than that after 10 s, and the reduction was accompanied by an increase in the excitability of M1 GABA b interneurons, which was more pronounced after 30 s of performing the task 5,13 . Interestingly, spinal excitability, which was tested by measuring cervicomedullary evoked potentials (CMEPs), increased during the waning of the tapping rate 14 , which is essentially different from the outcome when fatigue is caused by isometric exercise performed for the same duration and executed with the same body segment 14 .However, the description of how corticomuscular excitability changes with RRM fatigue development has not been performed, as previously done for isometric activities [15][16][17] . Another un-resolved point is whether the

Maximal-rate rhythmic repetitive movements cannot be sustained for very long, even if unresisted. Peripheral and central mechanisms of fatigue, such as the slowing of muscle relaxation and an increase in M1-GABAb inhibition, act alongside the reduction of maximal execution rates. However, maximal muscle force appears unaffected, and it is unknown whether the increased excitability of M1 GABAergic interneurons is an adaptation to the waning of muscle contractility in these movements. Here, we observed increased M1 GABAb inhibition at the end of 30 s of a maximal-rate finger-tapping (FT) task that caused fatigue and muscle slowdown in a sample of 19 healthy participants. The former recovered a few seconds after FT ended, regardless of whether muscle ischaemia was used to keep the muscle slowed down. Therefore, the increased excitability of M1-GABAb circuits does not appear to be mediated by afferent feedback from the muscle. In the same subjects, continuous (inhibitory) and intermittent (excitatory) theta-burst stimulation (TBS) was used to modulate M1 excitability and to understand the underlying central mechanisms within the motor cortex. The effect produced by TBS on M1 excitability did not affect FT performance. We conclude that fatigue during brief, maximal-rate unresisted repetitive movements has supraspinal components, with origins upstream of the motor cortex.

Understanding central fatigue during motor activities is important in neuroscience and different medical fields. The central mechanisms of motor fatigue are known in depth for isometric muscle contractions; however, current knowledge about rhythmic movements and central fatigue is rather scarce. In this study, we explored the role of an executive area (left dorsolateral prefrontal cortex [DLPFC]) in fatigue development during rhythmic movement execution, finger tapping (FT) at the maximal rate, and fatigue after effects on the stability of rhythmic patterns. Participants (n = 19) performed six sets of unresisted FT (with a 3 min rest in-between). Each set included four interleaved 30 s repetitions of self-selected (two repetitions) and maximal rate FT (two repetitions) without rest in-between.Left DLPFC involvement in the task was perturbed by transcranial static magnetic stimulation (tSMS) in two sessions (one real and one sham). Moreover, half of the self-selected FT repetitions were performed concurrently with a demanding cognitive task, the Stroop test. Compared with sham stimulation, real tSMS stimulation prevented waning in tapping frequency at the maximal rate without affecting perceived levels of fatigue. Participants' engagement in the Stroop test just prior to maximal FT reduced the movement amplitude during this mode of execution. Movement variability at self-selected rates increased during Stroop execution, especially under fatigue previously induced by maximal FT. Our results indicate cognitive-motor interactions and a prominent role of the prefrontal cortex in fatigue and the motor control of simple repetitive movement patterns. We suggest the need to approach motor fatigue including cognitive perspectives.