Separate analysis of the first (8 values for each condition) and the second half (7 values of each condition) of the postexercise measurement showed that values in facilitatory MEPs of the BR were markedly decreased during the first half (116.4 ± 23.1) but nearly normalized for the second half (123.7 ± 33.7) when compared with baseline (127.9 ± 30.7; cf. Fig. 3C). Neither inhibitory MEPs of the BR nor MEPs in the APB were altered in this analysis (data not shown). Thus, only the results of the first part of the postexercise measurement were taken for further analysis.
By stimulating the motor cortex and recording MEPs from a target muscle, TMS gives access to the entire neuronal pathway from the motor cortex to the muscle performing a task. Using the single-pulse technique, numerous studies have demonstrated changes in the central nervous system during and after exhaustive exercise (e.g., 4,6,12,13,16,22,27,30,33). From those studies, it was suggested that the reduction of MEP amplitudes after exhaustive exercise corresponds to muscle fatigue. From unchanged M-waves (6,33), H-reflexes (6), F-waves (33), and MEPs after magnetic stimulation of spinal roots (16), it was discussed that the mechanisms representing fatigue mainly originate upstream from the spinal level. Furthermore, the comparison between TMS and transcranial electrical stimulation (TES) is argued to point to a cortical origin of this phenomenon: TES is assumed to activate corticospinal neurons directly preferentially at the axon hillock. In contrast, TMS is known to elicit corticospinal discharges transsynaptically through intracortical interneurons (9,11). Thus, it was concluded that, under fatigue, depressed MEPs by TMS but not by TES were due to these cortical differences (6,33). In support, another parameter of TMS, the so-called “silent period” was assumed to reflect enhanced inhibition of intracortical neurons when it was found prolonged after fatiguing exercise (22,30). Nevertheless, some observations remain unclear from those studies: In fact, MEPs by TES under fatigue were also markedly reduced by 15–30% (6,33), which was half as much as was seen by TMS. The silent period after electrical brain stem stimulation also showed prolongation half as much as was seen after TMS (30). Investigating a fatiguing task, Mills and Thomson (24) described a significant decrease of M-waves but failed to find central fatigue by TMS. Thus, we have to assume that during muscle fatigue electrophysiological changes occur at several stages of the cortico-muscular pathway (e.g., (29)). Because fatigue is defined by a loss of muscle force, accompanying electrophysiological changes may or may not contribute to fatigue. Moreover, unchanged M-waves, F-waves, and H-reflexes do not exclude at all fatigue downstream from the spinal level.
Keeping this in mind, single-pulse TMS in combination with spinal reflexes, M-waves or TES as described in the above mentioned studies may not be a sufficient tool to assess central fatigue. For quantifying fatigue, TES, M-waves, H reflexes, F-waves, and spinal root stimulation are neither sensitive nor reliable enough and, in addition, these methods are inconvenient.
Some TMS studies with single-pulse technique found MEP facilitation shortly after the exercise followed by the MEP depression (e.g., 27). In our study, we did not find MEP facilitation in the target muscle, which is probably due to the time gap of 1–2 min between the last pull-up and the postexercise measurement.
What are the mechanisms underlying reversible reduction of ICF? Extensive pharmacological studies (e.g., 36) have shown that intracortical inhibition and facilitation as partially separate mechanisms (37) are mainly controlled by γ-aminobutyric acid (GABA)-ergic mechanisms. The decrease of ICF found here is reminiscent of reversible effects of benzodiazepines (35). But the effects of inhibition and facilitation within the motor cortex are obviously influenced by other brain areas since it has been described that, e.g., motor diseases as well as ischemic brain lesions (15,31) may influence ICI and ICF. Furthermore, glutamatergic agents as well as dopaminergic and antidopaminergic drugs are also believed to affect motor cortex neurons via GABA-ergic mechanisms (34,38). Thus, reduction of ICF indicates decreased motor cortex excitability upstream from the motor cortex output neurons. Further studies are needed to clarify the neurotransmitter systems and the higher brain regions involved in this mechanism.
To investigate the intracortical changes independently from spinal, α-motoneuronal, or peripheral alterations, we decided to keep the test MEP constant. Although the thresholds for eliciting small MEPs did not change significantly (Fig. 1B), higher test pulse intensities for the postexercise measurement were needed (Fig. 1C) to produce test MEPs of a given amplitude (0.75 mV in the BR). These findings are congruent with those TMS studies showing reduced MEPs after fatiguing exercise (see above). Nevertheless, with this adjustment of the test pulse, we could have induced the changes in ICF artificially. This, however, is unlikely, because only ICF but not ICI in the BR was changed. Even ICI and ICF in the APB remained unchanged, although APB test MEPs were markedly increased by this procedure (Fig. 1C). Why were test pulse MEPs in the BR reduced? This may refer to the mode of neuron activation by TMS: Brasil-Neto et al. (4) postulated a “decreased efficiency in the generation of the descending volleys in the motor cortex” under fatigue. It is known that one single TMS pulse like the test pulse used here elicits multiple descending volleys in one cortico-spinal neuron (so-called I-waves) (9,11). Those I-waves are controlled within the motor cortex and can be suppressed by GABA-ergic mechanisms (39). Thus, reduced MEP recruitment may be due to a GABA-mediated loss of cortico-spinal volleys reflecting fatigue of the motor cortex. Reduced ICF despite of the counterbalanced reduction of test MEP gives evidence that the observed effect was true.
From our data, we also may conclude that cortical fatigue occurred specifically for the muscle involved in the task. ICF was reduced for the BR but not for the APB of the same limb (Figs. 2 and 3). This seems to be in line with the study of Taylor et al. (30) showing silent period prolongation specifically for the muscle involved in an exercise, although it is not clear yet why McKay et al. (22) also found a silent period prolongation in a contralateral control muscle. Further studies have to focus on the distribution of fatigue within the ipsi- and contra-lateral cortex.
Support of the hypothesis that ICF reflects fatigue (see above) derives from the findings that the reduction of ICF was significantly correlated to the normalized work Wm (Fig. 4C). Subjects who were able to perform a great number of pull-ups, thus resulting in a high value of Wm, showed a marked decrease of ICF. In contrast, subjects who were only able to perform a small number of pull-ups showed only a slight decrease or even an increase of ICF. This might be due to the subject’s inability to perform pull-ups mainly because of low muscle capacity rather than fatigue, because a relatively high power is necessary to pull up one’s own body mass. The increase in ICF seems to be similar to what other authors described as postexercise facilitation under exercises before fatigue occurred (6,22,27,30). Nearly all subjects reached exhaustion under exercise and in subjects with high Wm the drop in ICF was marked (cf. Fig. 4, B and C). That means subjects with high capacity needed more reduction of power compared with subjects with lower capacity to meet the study’s criteria of fatigue. From our data, we conclude that the assessment of ΔICF may be a useful tool not only to demonstrate but to quantify fatigue of the motor cortex after exhaustive physical strain.
The reduction of ICF after exercise investigated here was reversible after approximately 5–8 min. Nevertheless, the course of ICF recovery, which was not investigated in detail here, should be the aim of another study.
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