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Is tDCS an Adjunct Ergogenic Resource for Improving Muscular Strength and Endurance Performance? A Systematic Review

Exercise performance is influenced by many physical factors, such as muscle strength and endurance. Particularly in the physical fitness and sports performance contexts, there are many types of ergogenic aids to improve muscular strength and endurance performance, with non-athletes and even athletes using illegal drugs to reach the top. Thus, the development of innovative methods to aid in exercise performance is of great interest. One such method is transcranial direct current stimulation (tDCS). A systematic search was performed on the following databases, until January 2019; PubMed/MEDLINE, SCOPUS, and Pedro database. Studies on tDCS for muscular strength and endurance performance improvement in non-athletes and athletes adults were included. We compared the effect of anodal-tDCS (a-tDCS) to a sham/control condition on the outcomes muscular strength and endurance performance. We found 26 controlled trials. No trial mentions negative side effects of the intervention. The data show differences between the studies investigating muscle strength and the studies evaluating endurance, with regard to successful use of tDCS. Studies investigating the efficiency of tDCS on improving muscular strength demonstrate positive effects of a-tDCS in 66.7% of parameters tested. In contrast, in studies evaluating the effects of a-tDCS on improving endurance performance the a-tDCS revealed a significant improvement in only 50% of parameters assessed. The majority of the data shows consistently influence of a-tDCS on muscular strength, but not to endurance performance. The results of this systematic review suggest that a-tDCS can improve muscular strength, but not to endurance performance.


INTRODUCTION
Exercise performance is influenced by many physical factors, such as muscle strength and endurance (Sleivert and Rowlands, 1996;Neumayr et al., 2003;McCormick et al., 2015). Particularly in the physical fitness and sports performance contexts, there are many types of ergogenic aids to improve muscular strength and endurance performance (Schubert and Astorino, 2012), with non-athletes and even athletes using illegal drugs to reach the top (Savulescu et al., 2004). Some years ago, sport scientists started to focus on the study of the brain as the central governor, and thus, regulates exercise with regards to a neurally calculated safe exertion by the body and how brain could limit or improve physical performance (Noakes, 2012). Since then, several studies investigated and showed the essential role of the brain in the determination of fatigue and muscular strength and endurance performance (Gandevia, 2001;Noakes, 2011aNoakes, ,b, 2012. Thus, the development of innovative methods to aid in exercise performance is of great interest (Noakes, 2012;Van Cutsem et al., 2017a). One such method is transcranial direct current stimulation (tDCS).
tDCS is a noninvasive technique that emits a weak electrical current that can promote excitation, through tonic depolarization of the membrane resting potential (anodic stimulus, a-tDCS), or cortical inhibition, by hyperpolarization of the membrane resting potential (cathodic stimulus, c-tDCS) (Nitsche and Paulus, 2000;Stagg and Nitsche, 2011), i.e., increase or decrease of spontaneous firing rate of neurons affected by the electrical current (Bikson et al., 2004;Rahman et al., 2013).
Last years, several researchers have begun to verify the effects of tDCS on physical performance in healthy individuals (Lattari et al., 2016(Lattari et al., , 2017(Lattari et al., , 2018bAngius et al., 2018). tDCS can be used as a neuromodulatory ergogenic resource for healthy individuals to change physical performance, such as lead to an increase in muscular strength (Lattari et al., 2016(Lattari et al., , 2017(Lattari et al., , 2018b, and endurance Lattari et al., 2018a), in both nonathletes Lattari et al., 2016Lattari et al., , 2017Lattari et al., , 2018aAngius et al., 2018) and athletes (Sales et al., 2016;Hazime et al., 2017;Vargas et al., 2018) that have been using tDCS during their training programs (Reardon, 2016;Edwards et al., 2017). In line with this, the objective of this systematic review was to verify whether tDCS is an effective ergogenic resource for muscular strength and endurance in non-athletes and athletes.

METHODS
The method of this study was designed and reported according to the recommendations of the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) (Green and Higgins, 2011) and the Cochrane Handbook for Systematic Reviews of Interventions (Liberati et al., 2009).
Studies were included according to Participants, Intervention, Comparison, Outcomes, and Setting (PICOS) inclusion criteria. Participants were healthy men and women adults, athletes, strength and endurance training practitioners or sedentary, with no history of mioarticular injury and no psychiatric illness. Intervention were used the effects of the anode stimulus of tDCS (a-tDCS). Comparators were sham tDCS (i.e., the placebo stimulus) or no interventions (i.e., control). Outcomes for both the muscular strength and endurance were evaluated from different points of view: (1) physical tasks that consist of uniarticular exercise or multiarticular exercise; (2) physical performance that was measured objectively as endurance time, total work performed, force production during a maximal voluntary contraction (MVC), peak power, mean power, and/or time to exhaustion. All these variables are considered the primary outcomes of our review. Study Design were only randomized and non-randomized trials, using either cross-over or parallel group designs, comparing an intervention encompassing a-tDCS with a sham group on muscle strength or no intervention.
We analyzed only studies published in English language. A systematic literature search was conducted between December 10−2018 and January 10−2019. The following databases were used: PubMed, ISI Web of Science, and Scopus. No filters were applied in the search.
The search was performed using the terms physical exercise, strength training, resistance training, endurance training, cycling, effort, physical exertion, fatigue, and athletic performance, individually combined with transcranial direct current stimulation and tDCS, in all databases.
Included important reports and reviews regarding tDCS and muscle strength or endurance were manually screened for additional relevant studies. Experts on the field, including authors from the reports, were also requested to suggest any additional trials in order to ensure that the review was as comprehensive and up-to-date as possible.
To facilitate the interpretation of our results, the findings were structured in two categories: (i) studies on the effects of tDCS on muscle strength performance (ii) studies on the effects of tDCS on endurance performance. This strategy was used due to the need to differ these physical tasks in terms of physiological responses (Sidhu et al., 2013). In addition, after revision of the studies, future perspectives for new researches were proposed based on the gaps in the existing literature and ethical and regulatory issues related to the use of tDCS as an enhancer for physical performance in athletes.

RESULTS
The results identified a total of 1,067 articles (511 in the PubMed, 543 in Scopus, and 13 in Pedro). After the removal process of duplicate articles (n = 25), a total of 1,042 articles remained. One thousand sixteen articles were removed by title and/or abstract. After the removal process, 26 articles were included for systematic review, 18 examining the effects of tDCS on muscular strength performance and 8 on endurance performance. Flow chart is presented in Figure 1.

The Effectiveness of tDCS on Improving the Endurance Performance
Regarding maximal incremental test, just one study investigated the effects of a-tDCS on endurance performance , and showed significant difference between a-tDCS and  Frontiers in Psychology | www.frontiersin.org Cycling, 20-min TT No improvements ↑ increased; time to exhaustion (TTE); time to failure (TTF); time trial (TT); Power output (PO); peak power output (PPO); a-tDCS, anodal transcranial direct current stimulation; cm 2 , square centimeter; mA-milliamps; min, minutes; s, seconds; MC, motor cortex; DLPFC, dorsolateral prefrontal cortex; OBF, orbitofrontal cortex; W, watts; %, percentage; NR, not reported.
Frontiers in Psychology | www.frontiersin.org sham condition, with an increase in peak power output (PPO) after a-tDCS. Another study examined the effects of a-tDCS on 30 s maximal-effort sprint cycling test, revealed no significant difference between a-tDCS and sham condition (Sasada et al., 2017). Four articles examined the effects of a-tDCS on TTE (Angius et al., 2015;Vitor-Costa et al., 2015;Barwood et al., 2016;Lattari et al., 2018a). Two studies showed significant differences between a-tDCS and sham (Vitor-Costa et al., 2015;Lattari et al., 2018a), with increase in endurance time after a-tDCS, while two study did not reveal significant difference (Angius et al., 2015;Barwood et al., 2016). Two studies investigated the effects of a-tDCS on TT (Barwood et al., 2016;Holgado et al., 2019), with no study demonstrating significant difference between a-tDCS and sham condition. In addition, one study evaluated the effects of a-tDCS on TTF, with significant difference between a-tDCS and sham conditions. The authors showed an increase in endurance time after a-tDCS (Angius et al., 2018).

DISCUSSION
This review aimed to discuss the potential effects of tDCS as an ergogenic resource for muscular strength and endurance performance. The data of 26 controlled trials were analyzed (see Tables 1, 2). No trial mentions negative side effects of the intervention. The data show differences between the studies investigating muscle strength and the studies evaluating endurance, with regard to successful use of tDCS. Studies investigating the efficiency of tDCS on improving muscular strength demonstrate positive effects of a-tDCS in 66.7% of parameters tested. In contrast, in studies evaluating the effects of a-tDCS on improving endurance performance the a-tDCS revealed a significant improvement in only 50% of parameters assessed. The majority of the data shows consistently no influence of a-tDCS on muscular strength, but not to endurance performance. We will also discuss the potential directions of futures studies.
Due to the complex process which is the exercise practice, several brain areas may be involved in exercise regulation/limitation, and thus, a justification for the use of tDCS for performance improvement. However, most studies on tDCS and exercise performance and sports are not clear with respect to their hypotheses of why applying tDCS in a particular area of the brain for improving performance, such as the primary motor cortex (M1), the dorsolateral prefrontal cortex (CPFDL), and the insular cortex (IC). Regarding brain areas, M1 is the most related to exercise performance due to its role in motor execution. Studies have consistently shown that central fatigue can compromise the physical performance of exercises of small muscle groups (e.g., elbow flexion), as well as exercises of large muscle groups (e.g., cycling). Specifically, spinal and supraspinal factors, such as reduced excitability of the motorneuron pool and the inability or limited ability of M1 and other supraspinal areas to increase the neural drive to compensate for this decrease in spinal excitability leads to decreased muscle capacity to produce strength/power and thus cause fatigue (Gandevia, 2001;Taylor and Gandevia, 2008;Taylor et al., 2016). Therefore, a reason to use tDCS over M1 would increase the excitability of it, which could result in sustained neural activity to the motor neuron, delay in the decrease of the neural unit to the active muscle and thus improve performance. In addition, other possible reasons for the application of tDCS over M1 could be modulate the pain perception. However, this mechanism still is unclear. A possible reason to direct M1 to pain modulation would be due to its connections with the insula and thalamus, as demonstrated in animal studies (Stepniewska et al., 1994). In addition, the a-tDCS in M1 increases the sensory and pain thresholds in healthy individuals as well as the level of pain in chronic pain patients (Vaseghi et al., 2014). In this regarding, it is suggested that exercise-induced pain plays a fundamental role in the regulation of performance, where individuals with better ability to tolerate or overcome pain would be more successful (Mauger, 2013). Therefore, the application of tDCS in M1 can also improve performance through exercise-induced pain attenuation.
With regard to PFC, whose main function is the cognitive control of behavior, seems to play an important role in processing internal and external cues related to the exercise performed (Robertson and Marino, 2016). PFC exerts a top-down influence that can result in changes of rhythm to complete the task, with prolongation of the motor output, slowing up the end of the exercise or the shutdown of the motor units, causing the end of the exercise (Robertson and Marino, 2016). Thus, the psychobiological model proposes this task of disengagement (that is, the end of the exercise) as a decision-making process based on the effort that depends on the motivation (for example, the maximal effort that a person is willing to exercise), perception of effort, knowledge of the endpoint of the exercise and distance/time remaining, and previous experience/memory of effort perception during exercise varying intensity and duration (Pageaux, 2014). A systematic review has confirmed that interventions aimed at decreasing the ability of PFC to exert control over bodily signals during exercise, such as mental fatigue (e.g., performing a cognitively prolonged task) may reduce endurance performance (Van Cutsem et al., 2017b). In fact, what has been observed is that there is a decrease in PFC oxygenation before the initiation of fatigue (Rupp and Perrey, 2008;Rooks et al., 2010). Therefore, the application of tDCS in the PFC could strengthen the ability of this region to disregard interoceptive cues (i.e., body signals), keeping the volitional drive to M1 and thus delaying the disengagement of the task (i.e., at the end of the exercise).
Another target area of tDCS studies on physical performance is the insular cortex (IC), considered as a responsible for cardiac autonomic control. Several types of studies indicate that the right IC is responsible for sympathetic modulation while the left IC is responsible for the parasympathetic modulation (Oppenheimer et al., 1992;Napadow et al., 2008). IC is a deep brain area, and theoretically it is modulated by tDCS through common connections with the temporal cortex (TC). For example, computational modeling and experimental studies showed that tDCS applied to left TC modulated IC activity, resulting in increased parasympathetic modulation at rest and during exercise (Montenegro et al., 2011;Okano et al., 2015). Within this context, the parasympathic branch is the responsible for modulating cardiac autonomic control at rest and when exercise begins a progressive decrease in modulation is observed until its complete withdrawal.
Concerning the different brain areas stimulated, studies on tDCS show opposite results and a high variability regarding the effects on muscular strength and endurance performance. The high inter-individual variability, i.e., responders vs. nonresponders, to tDCS would be a possible explanation to the variance in outcomes (López-Alonso et al., 2015). Other factors like the different electrode montages used (see Tables 1, 2) and stimulation parameters (see Tables 3, 4) also can have contributed to mixed result. Furthermore, due to differences in stimulation parameters, such as electrode size and position, even as the low focality of tDCS (Miranda et al., 2013), other brain areas beyond the target area could be affected by the electric current from tDCS, changing the results completely. Overall, tDCS seems to enhance muscular strength and endurance performances.
Although there are many differences in terms of experimental design and physical task performed, some common characteristics can be found: (i) primary motor cortex (M1) has been the most targeted area; (ii) a-tDCS was delivered main before the physical task; (iii) most of the studies applied 20 min of stimulation at 2 mA with an active electrode size of 35 cm 2 . In relation to neuromuscular parameters, a-tDCS generally increased corticospinal excitability (Cogiamanian et al., 2007;Williams et al., 2013;Hendy and Kidgell, 2014;Frazer et al., 2017). Physiological responses during exercise did not show consistent changes after a-tDCS. Notably, when perceptual responses were measured, the improvement in physical performance induced by CTEF was often associated with a lower perceived exertion (Williams et al., 2013;Okano et al., 2015;Angius et al., 2016Angius et al., , 2018Lattari et al., 2018b) while muscle pain did not change. The neurophysiological mechanisms that support the effect of a-tDCS on improving physical capacity are still unclear.
With respect to resistance, Cogiamanian et al. (2007) suggested that a-tDCS could improve subjects' motivation, reduce muscular pain, and modulate muscle synergy. However, none of the proposed mechanisms and corresponding parameters were monitored. Other authors propose that the improvement in endurance performance after a-tDCS could be due to increased neural drive and a reduction in supraspinatus fatigue (Williams et al., 2013;Vitor-Costa et al., 2015). Other authors have suggested that a-tDCS could influence sensorimotor integration and associated cognitive demand without altering the motor command (Abdelmoula et al., 2016). Angius et al. (2016Angius et al. ( , 2018 proposed that, due to the increase in a-tDCS-induced corticospinal excitability, fewer excitatory stimuli for M1 were required to produce the same submaximal force or power. As perceived exertion seems to depend on excitatory inputs from the supplemental motor area (SMA) and other brain regions (de Morree et al., 2012;Zenon et al., 2015), a reduction in such inputs would result in a lower perception of effort. It should be noted, however, that two studies reported improvements in endurance performance without significant changes in corticospinal excitability (Abdelmoula et al., 2016;Angius et al., 2016). This is not surprising, since previous studies have demonstrated a considerable variability in corticospinal response after tDCS over the motor cortex (MC) (Wiethoff et al., 2014;Madhavan et al., 2016).
Studies that investigated the effects of tDCS on muscle strength indicate that performance improvement was achieved both by increased corticospinal excitability and by reduced shortinterval intracortical inhibition and increased cross-activation (Hendy and Kidgell, 2014;Frazer et al., 2017). Other studies suggest that the improvement in workload was obtained by the reduction in the perception of effort (Lattari et al., 2016(Lattari et al., , 2018b. These mechanisms behind the tDCS's ergogenic effect remain unclear and should be interpreted with caution, since none of these studies monitored brain activity during exercise following tDCS.

Limitations and Future Directions
According to the rapid increase in the tDCS studies and muscular strength and endurance performance, important methodological limitations need to be considered. The different methodological characteristics of the experiments imply caution in interpret results related to effectiveness of tDCS as ergogenic aid. The standardization of methodological variables such as montage of electrodes, current intensity, session duration and other details, is essential to provide interesting insights about the real effects of tDCS on exercise and sport performance.
In addition, the mechanisms responsible for the improvements in muscular strength and endurance performances are still unclear. In line with this, an interest question is what results in the transient improvement in muscular strength and endurance performance? It seems that the modulation of corticospinal excitability or other targeted brain areas following tDCS would be the responsible for that improvement. Nevertheless, few studies examined corticospinal or brain activity following or during tDCS. Other technicality of tDCS is the low spatial resolution of the induced electric field in the brain when compared to transcranial magnetic stimulation (TMS) (Wagner et al., 2007a,b;Miranda et al., 2013), which can affect the functioning of certain brain areas beyond the target areas. The small sample found in the studies is other important point that can increase the probability of false positive results (Button et al., 2013). Lastly, the lack of appropriate blinding methods in most studies (see Tables 3, 4) should also be considered, since unapproved blinding procedure can lead to unexpected and confounding psychological effects, making difficult the interpretation of the results (Kessler et al., 2012;Fonteneau et al., 2019).

CONCLUSION
The results of this systematic review suggest that a-tDCS can improve muscular strength, but not to endurance performance. Nevertheless, evidence is insufficient to guarantee its effectiveness. New studies are required to assess the long-term effects of tDCS application combined with exercise training, whether with athletes or nonathletes. Despite tDCS is still considered a new tool in exercise and sport performance, it seems to have potential to improve performance. In line with this, more rigorous and extensive experimental studies are needed in order to better understand possible side effects from either regular use or abuse. Other important point that is needed is doing more studies with larger samples, appropriate blinding methods and techniques to examine neurophysiological mechanisms of tDCS.

AUTHOR CONTRIBUTIONS
SM and PJ designed the study, acquired and analyzed the data, and wrote the first draft of the paper. VA and JV helped to design the study, to organize the data acquired, and to discuss the first draft of the paper.