In the present study, for the first time to the best of our knowledge, the effects of anodal-tDCS over the M1 and DLPFC areas, which are important brain regions contributing to the physical and cognitive function, on endurance and cognitive performance and physiological responses under hypoxic condition were investigated. As a novel finding, we observed that the participants had a significantly longer TTE under hypoxia (O2 = 13% ⋍ 3500m altitude) after the left DLPFC tDCS, but not M1, compared to the sham condition. Interestingly, the longer TTE was accompanied by a higher EMG amplitude in the VM muscle, a lower RPE, and higher affective responses and arousal.
It has already been well documented that hypoxia can have detrimental effects on physical performance (in particular endurance performance) and cognitive function (28, 29, 31, 33). Several mechanisms at both central and peripheral levels have been proposed to bring about this hypoxia-induced decrement in the body’s capacity to work at its optimum level, such as the perturbation in neurovascular coupling which is considered the most crucial mechanism by which the brain works properly, decreased excitatory drives from the brain to the periphery, reduced O2 delivery to the mitochondria of the working muscles, and the augmentation in the firing of mechano- and metabo-sensitive group III and IV muscle afferents (32, 33, 35). These mechanisms have an indispensable implication for endurance performance since it has been shown that the capacity to perform an endurance task is highly sensitive to change in the abovementioned mechanisms even in the normoxic condition (26). Interestingly, recent findings have proposed that in hypoxia, particularly in severe hypoxia, the brain plays a more pivotal role in regulating endurance performance. In this context, Mira et al. (31), used terms such as the “brain-hypoxic effect” or the “hypoxia-sensitive central component of fatigue” to highlight the fact that in hypoxia, central mechanisms are the primary cause of developing fatigue and endurance performance deterioration. To support this notion, the recently developed psychobiological model (PBM) of fatigue during endurance exercise has presumed that the RPE and potential motivation (the psychological constructs of the PBM), which both are related to central levels in the brain, are the most important determinants of endurance performance (25). This could somehow explain the longer TTE in DLPFC condition under hypoxia in the present study since our results showed that the participants had lower RPE and higher affective responses and arousal (as has been demonstrated in the Circumplex Model of Affect in Fig. 5), in the DLPFC condition, compared to the sham condition.
Previous studies have demonstrated proposed that PFC, including the DLPFC, ventromedial and ventrolateral PFC, has a regulatory role in exercise performance by a higher order processing of interoceptive cues (i.e., afferent feedbacks), emotional and psychological drive (e.g., internal and external motivation, RPE, environmental features, among others) and deciding a relevant response (i.e., increase/decrease pace or stop exercise) (23, 24). In this regard, Angius et al. (6), reported that anodal tDCS targeting the left DLPFC improved endurance cycling performance in normoxia which was accompanied by a lower RPE. They attributed these findings to higher motivation as a result of the activation of the left DLPFC which is based on the PBM of fatigue during endurance performance (6). Moreover, Robertson and Marino (2016) proposed that the PFC (in particular its lateral region) would be involved in exercise tolerance and termination, along with other brain areas such as the anterior cingulate cortex, premotor area, and orbitofrontal cortex creating the pathways for interpreting afferent signals coming from different parts of the periphery (23). In this case, the PFC has been proposed to play a substantial role in integrating sensory afferent signals and providing suitable responses in a hierarchical manner leading to overruling inhibitory inputs and maintaining motor output (4, 20).
It is worth noting that under hypoxic condition, O2 insufficiency has an additive effect on exercise-related stressors which might in turn culminates in developing a more unpleasant environment negatively affecting exercise performance compared to the normoxic condition (26). Indeed, the role of different emotions such as pleasure-displeasure (known as Affect), arousal, motivation, and the sensation of pain in exercise tolerance have been emphasized in previous studies (23, 40). The PFC has been shown to integrate these emotions to regulate endurance performance. In the present study, we found more positive psychophysiological responses in the DLPFC tDCS condition compared to the sham. It seems that anodal tDCS targeting the left DLPFC has been able to provide a compensatory effect in the hypoxic condition by improving the function of the left DLPFC area possibly through both increasing the excitability of neural circuits beneath the stimulation site and increased oxygenation of this region by enhanced blood flow (1, 39). It seems to be a plausible scenario based on the psychobiological model of fatigue during endurance performance in which better psychophysiological responses such as higher motivation and better pleasure sensation delay the critical time point when an exerciser decides to stop endurance exercise as it has been conjectured that the disengagement from an endurance task is a cognitive decision-making process which might be regulated in DLPFC area (25).
The results of the present study also showed that there was no difference in the amplitude of EMG of the VL and RF muscles during a cycling endurance task under hypoxia among tDCS conditions. Conversely, the amplitude of EMG of the VM muscle was significantly higher only after DLPFC tDCS than the sham. The causative effect of tDCS on the muscle EMG has been a controversial topic as most of the studies did not see any effect of tDCS on the muscle EMG (6, 41, 42) while some recent findings suggest that tDCS might affect the muscle EMG (7, 21, 38, 43). In this sense, changes in the motor unit recruitment strategies as a result of brain stimulation have been suggested as the mechanism by which tDCS could induce its effect on muscle activity reflected by EMG (7, 38). Surprisingly, in previous studies, anodal tDCS of M1 has yielded the observed effect on muscle EMG while, in the present study, we saw a higher EMG amplitude in VM muscle in the DLPFC condition compared to sham, but not in the M1 tDCS. It’s not clear why the EMG amplitude was not affected by the M1 tDCS in the present study. One reason might be the fact that in the present study we did not use transcranial magnetic stimulation (TMS) which is the most standard method for hot spotting the precise region representing the motor area of the lower limb over the M1 for tDCS (17). It is worth mentioning that, however, the international 10–20 EEG system has been corroborated as a valid method for stimulating target areas in the brain in most of the previous studies (9, 15, 20, 21, 43). In addition, the demanding nature of the hypoxic condition might have had a regulatory role in the M1 response to the anodal tDCS. This latter raises an interesting question of whether the hypoxic condition could change the degree to which different areas of the brain such as M1 and PFC contribute to the neural drive to the working muscles. On the other hand, despite the need for further investigation to corroborate the causal influence of PFC on the motor unit recruitment strategies and neural drive to the periphery, it looks that anodal tDCS of the left DLPFC at the top of the motor hierarchy has been able to create a cascade from the PFC to M1 leading to a change in the recruitment and firing frequency of the target motor units which have been reflected in the EMG amplitude of the VM muscle in the present study while, the stimulation of M1 has not been able to compensate for the inhibitory afferent signals coming from different peripheral regions that are intensified due to the burden of the hypoxic condition (4, 7, 20, 23, 38).
In the present study, despite a higher CWST score in the DLPFC tDCS condition (Δ= 25.3%) compared to the sham, there was no significant difference in the IG score of the CWST among the conditions. However, a significantly shorter CRT was observed in the DLPFC tDCS condition compared to the sham after the exhaustion in the endurance task under hypoxia. Recent studies have shown mixed findings regarding cognitive function while exercising in hypoxia which accentuates that we are facing a more complex scenario compared to normoxia (30, 44–46). In this scenario, on one hand, it has been corroborated that cognitive function is compromised as the severity of hypoxia increases, most probably due to hypoxia-induced impairment in NVC which is the main mechanism of the brain O2 delivery (30, 35, 47). On the other hand, however, recent findings have demonstrated that moderate exercise could improve cognitive function even in moderate to severe hypoxia perhaps by increasing arousal through the noradrenergic and dopaminergic regulation (35, 45, 48, 49). Hence, it seems feasible that the balance between the positive effects of acute exercise and the negative effects of hypoxia determines the cognitive function in this situation (30). The incongruent Stroop test is deemed as a task requiring high cognitive effort involving the detection of interference between two parallel processes, making a decision while overlooking unrelated information, and the inhibition of habitual actions (50, 51). This emphasizes the fact that a proper brain function is necessary for precise information processing in such incongruent conditions.
In this context, Ochi et al. (52), showed that the hypoxic condition exacerbated the performance in the Stroop test and reduced executive function. In the present study, despite a little better performance under the DLPFC condition, it seems that the possible positive and synergistic effects of endurance exercise and brain stimulation were not able to overcome the detrimental effects of the neuromuscular fatigue and hypoxic condition. Astonishingly, the CRT in the DLPFC condition was significantly lower than the sham. This interesting finding made us assume that the nature of the cognitive task performed, concerning the extent to which it requires cognitive efforts, is another factor affecting the balance between exercise and hypoxia which in turn determines the cognitive function. In this particular case, probably, the additive effect of anodal tDCS targeting the left DLPFC and endurance exercise have been able to counteract the detrimental effects of hypoxia and the burden of reaching the point of failure. The findings of Abedanzadeh et al. (50), provide more support for this notion as they showed that anodal stimulation of the left DLPFC could boost information processing speed and the capacity of attention (reflecting in a reduced reaction time) leading to override the impact of the psychological refractory period. Alternatively, improved CRT performance after TTE under hypoxia in the DLPFC tDCS condition may represent that cognitive capacities were, at least in part, preserver with this specific montage, which in turn provided improved cognitive processing of exercise-related stimulus and greater top-down control, which, ultimately, maintained exercise for a longer duration. This would provide additional support for the role of the DLPFC and cognitive processing in exercise regulation (23, 24).
Finally, an important consideration regarding the results of the present study is the fact that in the M1 condition, contrary to some of the previous studies, in spite of a slight positive effect, there was no significant positive effect of the M1 tDCS on endurance and cognitive performance, psychophysiological and physiological responses to exercise in hypoxia. This is in line with a recent study by Machado et al. (2021), who found no significant effect of conventional and high-definition tDCS targeting M1 on physiological and psychophysiological response nor in endurance performance in normoxia in endurance-trained athletes (15). This raises an interesting topic of whether the response of different brain areas to tDCS might be modulated by environmental stressors. As such, it could be hypothesized that in the hypoxic condition where the perturbation in O2 delivery places a physical and cognitive burden on the body, the brain areas such as PFC that are more involved in the cognitive process might be more responsive to tDCS and play a more important role in regulating body’s capacity to work appropriately compared to M1. Nevertheless, future studies with a rigorous design are warranted to shed light on this topic and provide supporting mechanisms to confirm it.
Despite taking all necessary details into account to provide optimum control over the study procedure, caution must be taken when considering the findings of the present study because they are not free from the effects of limiting factors. In this study, we were not able to use TMS for hot spotting the lower limb representation in the M1 which might have affected the response of this region to tDCS. In addition, we were not able to use neurophysiological/neuroimaging measures that could provide more information concerning any changes induced in brain activity. Finally, to the best of our knowledge, this is the first study investigating the effect of tDCS on a variety of sports-related variables in hypoxia and accordingly, we were facing a dearth of information concerning the design of the study and also discussing our results with more mechanistic interpretations. On the other hand, this is the first study not only to assess the effect of tDCS on endurance exercise in hypoxia but also the first to directly compare two tDCS montages targeting different brain regions on whole-body exercise performance. The only previous study to compare stimulation of two brain regions with tDCS was performed by Radel et al. (20) who did not find any effect of either M1 or DLPFC tDCS on single elbow flexion isometric contraction sustained to task failure. Hence, the present study provides an important advance in current knowledge and expands possibilities for future research to test fatigue model predictions as well as the effectiveness of different tDCS protocols in different ambient conditions.