The development of fatigue has been an area of interest to athletes and scientists alike for many years. Often, particularly during prolonged exercise in the heat, there is no obvious peripheral reason for fatigue and the central nervous system is cited as the source. The mechanisms and potential manipulations of this fatigue remain largely unclear. Chapters Three and Four attempted to reduce the transport of the serotonin precursor tryptophan into the brain in order to reduce or delay serotonin synthesis and therefore increase exercise capacity. In Chapter Three branched-chain amino acid drinks were fed before and during prolonged cycling to exhaustion in the heat on two occasions and control drinks were fed on two other occasions. There was no effect of the branched-chain amino acids on exercise capacity and the intra-individual variability in seven of the eight participants was small. One participant did appear to cycle for longer on the branched-chain amino acid trials compared to the control trials. In Chapter Four a 104 g bolus of amino acids, designed to deplete plasma tryptophan concentration, was fed seven hours before a prolonged cycle to exhaustion in the heat. There was no difference in exercise capacity between the tryptophan depletion trial and the control trial in which tryptophan was also ingested. These findings suggest that the delivery of tryptophan to the central nervous system is not the only factor influencing the onset of fatigue. The investigation undertaken in Chapter Five looked at the serotonin transporter density on the blood platelets of current and retired international level athletes competing in either endurance or sprint running events and a sedentary control group. Using the platelet as an accessible and reliable model for the serotonergic neuron, the maximum number of binding sites was assessed using the radio-labelled serotonin reuptake inhibitor [3H]Paroxetine. Those currently training for endurance events had a greater number of binding sites than any of the other groups. This supports previous findings and suggests that endurance training can increase the number of serotonin transporters on blood platelet membranes. During resting heat exposure in Chapter Six, the application of a 1 % menthol solution to the skin of the forearms, back and forehead elicited a warming sensation in some individuals and a cooling sensation in other individuals, but never any change in skin or core temperature nor skin blood flow. A small proportion of individuals did not perceive any change in skin thermal sensation. Chapter Seven applied these findings to a pre-loaded twenty minute exercise performance test in the heat. It was hypothesised that those who perceived a warming effect may perform worse when a menthol solution was applied compared to a control solution and conversely, those who perceived a cooling sensation may perform better with a menthol solution than with a control solution. There was no difference in exercise performance between those who felt a warming sensation and those who felt a cooling sensation. Those who felt a warming sensation felt significantly warmer on the menthol trial than the control trial but this did not affect their performance. However, those who reported a cooling sensation tended to feel cooler on the menthol trial than the control trial, and there was a tendency for an improvement in performance on the menthol trial compared to the control trial. Due to the experimental protocols adopted in this thesis it was possible to assess the reliability of an exercise capacity test compared to an exercise performance test. Chapter Three showed a coefficient of variation of 11.0 ± 11.2 % and Chapter Four showed a 11.5 ± 12.4 % variability for exercise capacity tests. Chapter Seven showed a coefficient of variation in a pre-loaded time-trial exercise performance test of 3.9 ± 9.6 % suggesting that an exercise performance test may be more reliable than an exercise capacity test. However, the aims of an investigation are still likely to be the main factor influencing the choice of protocol. It seems likely that no single mechanism will be responsible for the cessation of exercise. The investigations undertaken in this thesis also highlight many avenues for future exploration.

The aim of this thesis was to directly test the key underpinnings of recent propositions for systems of central control of exercise regulation. Fatigue and exercise tolerance have traditionally been explained through peripheral mechanisms, such as excitation-contraction coupling failure and the inability to supply sufficient metabolic substrate to contracting muscle in order to meet increasing energy demand. More recently, models of central control, which are proposed to regulate exercise intensity in an anticipatory/feedforward manner, with the ultimate aim of avoiding physiological ‘catastrophe’, have received a great deal of attention. This thesis investigated several of the key requirements and mechanisms stated in these models. The central governor model (CGM) and teleoanticipation are stated to use a combination of prior experience and distance knowledge of an exercise bout to work in a feedforward manner, so that a pacing strategy is set before exercise commences which ensures the bout is completed in an optimum time but in the absence of premature fatigue. Study one examined the influence of distance knowledge, prior experience and distance feedback on the setting and regulation of a pacing strategy in 4 km time trial (TT) cycling in trained cyclists (n = 18). When performing 4 × 4 km TT intervals, it was found that prior experience of the exercise (in the absence of distance feedback and distance knowledge) allowed the creation of a pacing strategy that produced a performance which was as competitive as cyclists who were provided with prior experience, distance knowledge and distance feedback. The difference in TT completion time between groups (CON = feedback group, EXP = no feedback group) was reduced with subsequent TT (CON TT1 367 ± 21 s; EXP TT1 409 ± 45 s; CON TT2 373 ± 19 s; EXP TT2 389 ± 30 s; CON TT3 375 ± 18 s; EXP TT3 383 ± 26 s; CON TT4 373 ± 20 s; EXP TT4 373 ± 14 s), so that by the final TT, completion time between groups was almost exactly the same. It was concluded that when sufficient prior experience is attained in the absence of distance knowledge and feedback, a successful pacing strategy can be set. In order for pacing to be set prior to an exercise bout and adjusted in a feedforward/anticipatory manner during exercise, an internal mechanism must exist which monitors the passage of time. Study two examined the accuracy and robustness of this ‘internal clock’ by assessing cyclist’s (n = 16) ability to gauge the distance they had cycled during repeated 4 km and 6 km TT. The internal clock was shown to be inaccurate to absolute measures of distance, but showed a calibration capacity following experience of a TT of unknown distance (24.6 ± 18.2 % error in distance judged completed vs. 8.2 ± 5.5 % error in distance judged completed). This process was fragile and occurred in the absence of any significant performance improvement. It was concluded that relative quantities appear more important in creating a pacing strategy, and that times are of greater importance than distances. Study three examined the influence of comparative performance feedback in a field setting in 4 km track TT cycling in trained cyclists (n = 5). Correct feedback produced a significantly faster TT time (t4 = -3.10, p < 0.05) than non-contingent feedback (341 ± 8 s vs. 350 ± 12 s), with differences in mean lap speed apparent between the conditions at the start of the TT (t4 = 4.71, p < 0.05) and at the end of the TT (t4= 3.45, p < 0.05; t4 = 3.30, p < 0.05). The study provided empirical support for the assumption that performance feedback is advantageous during exercise and provided insights into past and present exercise comparison and its role on the setting of a pacing strategy. A central component of the CGM and theories of central exercise regulation is the role of afferent feedback during exercise and the premature termination of exercise before a true maximum intensity has been reached. Study four used acetaminophen to blunt cyclists’ (n = 13) pain response during ten mile (16.1 km) TT in order to disrupt the afferent feedback processes. When using acetaminophen, cyclists produced significantly faster (t12 = 2.55, p < 0.05) TT completion times (1575 ± 96 s) than under a placebo condition (1605 ± 122 s). When using acetaminophen, cyclists had a higher power output during the middle section of the TT (F1, 12 = 4.79, p < 0.05), yet showed no significant difference in RPE (F1,12 = 0.72, p > 0.05) or pain scores (F1,12 = 0.30, p > 0.05). It was concluded that acetaminophen reduced levels of pain during the TT, thereby disrupting the comparative afferent feedback mechanism and allowing cyclists access to a ‘metabolic reserve’. The research presented has advanced our knowledge and supported propositions of models of central control and regulation during exercise. The research has provided further insight in the role of prior experience, distance knowledge, distance feedback, the internal clock, performance feedback and afferent feedback on the setting and maintenance of a pacing strategy in 4, 6 and 16.1 km TT cycling.

Neuromuscular fatigue, even that caused by light submaximal exercise, impairs motor performance and alters motor planning. This impairment is evident in muscle reaction time, force production capacity and joint position sense as well as in more complex tasks such as postural stability. When an individual is fatigued their postural sway increases and they are less able to recover from unexpected postural perturbations. Although a large number of work-related falls are caused by fatigue every year, the mechanisms behind the instability are not well understood. Since postural control does not require a large amount of muscular strength it is unclear whether the post-fatigue changes in posture are due to impairment within the muscle fibers or are a central modification of the motor plan used to execute the movement task. In order to better understand neuromuscular fatigue researchers have labeled fatigue occurring within the muscles ‘peripheral fatigue’ and that occurring within the central nervous system ‘central fatigue’. At the onset of a muscular contraction peripheral and central fatigue develop simultaneously, making it difficult to clearly articulate the role that they each play in the decreased motor performance found post-fatigue. Techniques such as transcranial magnetic and electrical nerve stimulation quantify the contribution of central fatigue to the decreased maximal force production but the impact on motor planning is still not well understood. Therefore, the primary aim of this doctoral dissertation was to isolate central fatigue from peripheral muscle fatigue and to compare the influence that it may have on dynamic postural control to the changes caused by general fatigue of the local postural muscles. This overarching research goal was accomplished through five separate studies. The first study in this dissertation determined that at least seven postural trials needed to be performed to ensure that the participants had fully adapted to the postural task before the fatigue protocol was implemented. Experiment 2 characterized the fatigue produced by bilateral, isometric ankle muscle contractions and examined the recovery of the central and peripheral changes throughout a ten-minute post-fatigue recovery period. The results demonstrated that the alternating maximal ankle plantar and dorsiflexor contractions created central and peripheral fatigue. Central fatigue recovered within the first two minutes post-fatigue while peripheral fatigue lasted throughout the ten-minute post-fatigue period. Experiment 3 analyzed the impact of this ankle muscle fatigue protocol on the postural response to a continual, externally driven, sinusoidal oscillation of the support platform. In this study the fatigued participants were able to stabilize their center of mass displacement using two different anticipatory postural responses to the backwards perturbation whereas all of the participants used the same anticipatory response to the forwards perturbation. All three postural responses became progressively more conservative throughout the ten-minute post-fatigue period, despite the rapid recovery of the ankle force production capacity. The final two studies characterized the fatigue produced during a continuous, isometric forearm contraction and assessed the impact on ankle motor performance (Experiment 4) and on postural control (Experiment 5). Peripheral fatigue created in the forearm muscles during this contraction remained throughout the post-fatigue testing session. Central fatigue and a decreased maximal force production capacity were quantified in both the forearm and ankle plantarflexor muscles immediately after the forearm contraction, indicating that central fatigue created during the forearm exercise crossed over to the distal and unrelated ankle plantarflexor muscles. The influence of the central fatigue created during the forearm contraction affected the anticipatory postural response in a similar way to the fatigue created by the ankle fatigue protocol. The post-fatigue modification of the postural response dissipated as the central fatigue recovered. Taken together, these five studies extend the current understanding of how exercise induced neuromuscular fatigue modifies the central nervous system’s control of complex motor tasks.

Fatigue is defined as an exercise-induced decrease in maximal voluntary force produced by a muscle. Fatigue may arise from central and/or peripheral mechanisms. Supraspinal fatigue (a component of central fatigue) is defined as a suboptimal output from the motor cortex and measured using transcranial magnetic stimulation (TMS). Reductions in O2 supply (hypoxia) exacerbate fatigue and as the severity of hypoxia increases, central mechanisms of fatigue are thought to contribute more to exercise intolerance. In study 1, the feasibility of TMS to measure cortical voluntary activation and supraspinal fatigue of human knee-extensors was determined. TMS produced reliable measurements of cortical voluntary activation within- and between-days, and enabled the assessment of supraspinal fatigue. In study 2, the mechanisms of fatigue during single-limb exercise in normoxia (arterial O2 saturation [SaO2] ~98%), and mild to severe hypoxia (SaO2 93-80%) were determined. Hypoxia did not alter neuromuscular function or cortical voluntary activation of the knee-extensors at rest, despite large reductions in cerebral oxygenation. Maximal force declined by ~30% after single-limb exercise in all conditions, despite reduced exercise time in severe-hypoxia compared to normoxia (15.9 ± 5.4 vs. 24.7 ± 5.5 min; p < 0.05). Peripheral mechanisms of fatigue contributed more to the reduction in force generating capacity of the knee-extensors following single-limb exercise in normoxia and mild- to moderate-hypoxia, whereas supraspinal fatigue played a greater role in severe-hypoxia. In study 3, the effect of constant-load cycling exercise to the limit of tolerance in hypoxia (SaO2 ~80%) and normoxia was investigated. Time to the limit of tolerance was significantly shorter in hypoxia compared to normoxia (3.6 ± 1.3 vs. 8.1 ± 2.9 min; p < 0.001). The reductions in maximal voluntary force and knee-extensor twitch force at task-failure were not different in hypoxia compared to normoxia. However, the level of supraspinal fatigue was exacerbated in hypoxia, and occurred in parallel with reductions in cerebral oxygenation and O2 delivery. Supraspinal fatigue contributes to the decrease in whole-body exercise tolerance in hypoxia, presumably as a consequence of inadequate O2 delivery to the brain.

Neuromuscular fatigue, even that caused by light submaximal exercise, impairs motor performance and alters motor planning. This impairment is evident in muscle reaction time, force production capacity and joint position sense as well as in more complex tasks such as postural stability. When an individual is fatigued their postural sway increases and they are less able to recover from unexpected postural perturbations. Although a large number of work-related falls are caused by fatigue every year, the mechanisms behind the instability are not well understood. Since postural control does not require a large amount of muscular strength it is unclear whether the post-fatigue changes in posture are due to impairment within the muscle fibers or are a central modification of the motor plan used to execute the movement task. In order to better understand neuromuscular fatigue researchers have labeled fatigue occurring within the muscles ‘peripheral fatigue’ and that occurring within the central nervous system ‘central fatigue’. At the onset of a muscular contraction peripheral and central fatigue develop simultaneously, making it difficult to clearly articulate the role that they each play in the decreased motor performance found post-fatigue. Techniques such as transcranial magnetic and electrical nerve stimulation quantify the contribution of central fatigue to the decreased maximal force production but the impact on motor planning is still not well understood. Therefore, the primary aim of this doctoral dissertation was to isolate central fatigue from peripheral muscle fatigue and to compare the influence that it may have on dynamic postural control to the changes caused by general fatigue of the local postural muscles. This overarching research goal was accomplished through five separate studies. The first study in this dissertation determined that at least seven postural trials needed to be performed to ensure that the participants had fully adapted to the postural task before the fatigue protocol was implemented. Experiment 2 characterized the fatigue produced by bilateral, isometric ankle muscle contractions and examined the recovery of the central and peripheral changes throughout a ten-minute post-fatigue recovery period. The results demonstrated that the alternating maximal ankle plantar and dorsiflexor contractions created central and peripheral fatigue. Central fatigue recovered within the first two minutes post-fatigue while peripheral fatigue lasted throughout the ten-minute post-fatigue period. Experiment 3 analyzed the impact of this ankle muscle fatigue protocol on the postural response to a continual, externally driven, sinusoidal oscillation of the support platform. In this study the fatigued participants were able to stabilize their center of mass displacement using two different anticipatory postural responses to the backwards perturbation whereas all of the participants used the same anticipatory response to the forwards perturbation. All three postural responses became progressively more conservative throughout the ten-minute post-fatigue period, despite the rapid recovery of the ankle force production capacity. The final two studies characterized the fatigue produced during a continuous, isometric forearm contraction and assessed the impact on ankle motor performance (Experiment 4) and on postural control (Experiment 5). Peripheral fatigue created in the forearm muscles during this contraction remained throughout the post-fatigue testing session. Central fatigue and a decreased maximal force production capacity were quantified in both the forearm and ankle plantarflexor muscles immediately after the forearm contraction, indicating that central fatigue created during the forearm exercise crossed over to the distal and unrelated ankle plantarflexor muscles. The influence of the central fatigue created during the forearm contraction affected the anticipatory postural response in a similar way to the fatigue created by the ankle fatigue protocol. The post-fatigue modification of the postural response dissipated as the central fatigue recovered. Taken together, these five studies extend the current understanding of how exercise induced neuromuscular fatigue modifies the central nervous system’s control of complex motor tasks.

While fatigue is a common daily phenomenon, the exact relationship between perception of effort and fatigue is still unknown. Existing tools for assessing perception of effort are effectively limited to whole body exercise, while current methods for assessing voluntary activation are painful and not feasible for clinical application. The main aims of this thesis were to evaluate existing methodologies for their appropriateness in assessing perception of effort and voluntary activation following isolated muscle function testing, and to examine the relationship between subjective perception of effort and objective changes in the healthy motor control system. The implementation of reliable and valid assessment tools in clinical practice may enable clarification of the pathogenesis of many neurological conditions that have chronic fatigue as a key feature. Four studies of within-subjects repeated measures design have been conducted. Sixtynine healthy volunteers were recruited among staff and students of Brunel University. Magnetic stimulation was tested as a valid alternative to electrical stimulation in the conventional single-pulse Twitch Interpolation Technique. The 0–10 Numeric Rating Scale (NRS) was also tested for its reliability and validity in assessing the perception of effort during isometric exercise of elbow flexors. The changes of perception of effort following a submaximal elbow flexion fatiguing task, as well as following transcranial direct current stimulation (tDCS) over the motor cortex were also tested. The main findings showed significant differences between peripheral and magnetic stimulation in conventional single-pulse Twitch Interpolation Technique. The 0–10 NRS demonstrated linear properties and reported excellent test-retest reliability and good concurrent criterion validity in recording perception of effort under repeated isometric contractions of elbow flexors. Ten minutes of a submaximal intermittent isometric fatiguing exercise produced a significant elevation in rating of perceived effort, which was associated with central and peripheral neurophysiological changes of the motor control system. In contrast, perception of effort did not change significantly following 10 minutes of tDCS. The major findings of this thesis suggest the 0–10 NRS is a valid and reliable scale for rating perception of effort in healthy individuals. Further testing of the scale on patients is needed to establish its validity in clinical settings. Additionally, the findings indicate a substantial role of perception of effort in the voluntary motor control system. However, further research towards revealing the underlying mechanisms of perceived effort regulation in both health and disease is required.

O objetivo do presente estudo foi analisar os efeitos da execução prévia de exercício físico e cognitivo sobre os componentes central e periférico da fadiga neuromuscular durante um teste contrarrelógio de 4 km de ciclismo. Para tanto, oito ciclistas treinados (n = 8) participaram de três diferentes estudos. No estudo 1, os atletas realizaram o teste contrarrelógio após assistir documentário (CON) ou após tarefa cognitiva (TC). No estudo 2, o teste de 4 km de ciclismo foi realizado após 100 drop jumps (DJ), 48 horas após 100 drop jumps (48h-DJ) e sem a realização prévia de exercício (CON). No estudo 3, o teste contrarrelógio foi realizado após fadiga prévia de membros superiores (FB) e inferiores (FP) e sem fadiga prévia (CON). Em todos os estudos, parâmetros de fadiga central e periférica foram avaliados por meio da técnica de estimulação elétrica no nervo femoral em repouso, pré e pós 4km de ciclismo. Estudo 1: O desempenho foi similar (P> 0,05) entre CON (376 ± 26,9 s) e TC (376,3 ± 26 s). Do mesmo modo, não encontramos diferenças significativas (P> 0,05) para parâmetros de fadiga central e periférica entre CON e TC. Estudo 2. O desempenho foi significativamente (P< 0,05) prejudicado em DJ (-2,3%) e houve uma tendência em 48h-DJ (-1,8%). A redução no desempenho em 48h-DJ foi devido à menor potência na parte inicial da prova (P< 0,05). Em DJ a piora no desempenho foi em decorrência de menor potência (P< 0,05) na parte inicial e final da prova. Houve uma exacerbada (P< 0,05) fadiga periférica após o contrarrelógio em DJ (1Hzpot= -44,7%) comparado com CON (1Hzpot= -20,1%). Além disso, significante fadiga de baixa frequência foi observada em DJ comparado com CON. Por outro lado, parâmetros de fadiga central e periférica apresentaram valores similares entre CON e 48h-DJ (P> 0,05). No entanto, foi encontrado aumento significativo (P< 0,05) na dor muscular tardia em 48hDJ comparado com CON e DJ. Estudo 3: O desempenho foi reduzido em FP (-2,3%) e FB (-1,5%) quando comparado com CON. O menor desempenho nas condições FP e FB foi acompanhado por redução na potência (P< 0,05) na parte inicial (condição FP) e na parte final (condições FP e FB) a prova. Ao final dos 4 km de ciclismo, os participantes apresentaram menor (P< 0,05) fadiga periférica em FB (1Hzpot= -11,9%) comparado com CON (1Hzpot= -20,1%). Em FP, houve maior fadiga periférica em comparação a condição CON e FB. Em conclusão, os resultados destes estudos sugerem que apenas a execução prévia de exercício envolvendo a musculatura utilizada no ciclismo promove alterações nos componentes periféricos da fadiga neuromuscular após 4 km de ciclismo / The aim of this study was to analyze the effects of previous execution of physical exercise and cognitive on the central and peripheral components of the neuromuscular fatigue during a 4 km cycling time trial. Eight trained cyclists (n = 8) participated of three different studies. In study 1, the athletes performed the 4 km cycling time trial test after watching a documentary (CON) or after a cognitive task (CT). In study 2, the 4-km cycling test was performed after 100 drop jumps (DJ), 48 hours after 100 drop jumps (48h-DJ) and without previous exercise (CON). In study 3, the time trial was performed after pre-fatigue of the upper (FU) and lower (FL) body and without prefatigue (CON). In all studies, central and peripheral fatigue parameters were evaluated via electrical stimulation in femoral nerve at rest, before and after 4km cycling. Study 1: Performance was similar (P> 0.05) between CON (376 ± 26.9 s) and TC (376.3 ± 26 s). Likewise, we found no significant differences (P> 0.05) for parameters of central and peripheral fatigue between CON and CT. Study 2: Performance was significantly (P< 0.05) impaired in DJ (-2.3%) and there was a trend in 48h-DJ (-1.8%). This reduction in performance in 48h-DJ was due to a lower power at first part of the time trial (P< 0.05). In DJ condition, loss in performance was due to lower power (P< 0.05) at the start and end phases of the test. There was exacerbated (P <0.05) peripheral fatigue after the time trial in DJ (1Hzpot = -44.7%) compared to CON (1Hzpot = 20.1%). Furthermore, a significant low frequency fatigue was observed in DJ compared to CON. On the other hand, central and peripheral fatigue parameters showed similar values between CON and 48h-DJ (P> 0.05). However, a significant increase in delayed onset muscle soreness was found in 48h-DJ than CON and DJ. Study 3: Performance was reduced in FU (-2.3%) and FL (-1.5%) compared to CON. The lowest performance was accompanied by a reduction in power (P< 0.05) in the initial (FL) and final (FL and FU phases of the time trial. After 4 km cycling, participants had a lower (P< 0.05) peripheral fatigue in FU (1Hzpot = -11.9%) compared with CON (1Hzpot = -20.1%). In FL, there was a greater peripheral fatigue compared to CON and FB condition. In conclusion, the results of these studies suggest that only the previous execution of exercise involving the muscles used in cycling causes changes in the peripheral components of the neuromuscular fatigue after 4 km of cycling

Performance during prolonged exercise capacity diminishes with increasing temperatures. The onset of fatigue under these conditions is not adequately explained by peripheral mechanisms. Recently, drugs which inhibit the reuptake of dopamine and noradrenaline in the brain have been found to improve exercise performance in warm conditions. The aim of this thesis was to further explore and characterise the role of these neurotransmitters during prolonged exercise in warm conditions by manipulating their reuptake or synthesis. The first series of experiments were designed to further investigate the effects of bupropion, a dopamine and noradrenaline reuptake inhibitor, which has been found to improve performance in warm conditions. To explore gender differences in response to acute bupropion administration, the effects of bupropion on prolonged exercise performance in warm conditions in women was investigated in Chapter 3. The results of this study suggest that during the follicular phase of the menstrual cycle, acute administration of bupropion improves exercise performance. To determine whether there are any dose-dependent effects of bupropion, the experiment in Chapter 4 was designed to test three different doses of bupropion. Exercise performance was only improved for the maximal dose, suggesting a threshold for the performance effects of bupropion. Catecholamine precursors do not appear to improve exercise performance as consistently as reuptake inhibitors. In agreement with previous studies, the dopamine precursor L-DOPA did not affect exercise performance in warm conditions in Chapter 5. In Chapter 6 the effect of the atypical antidepressant nutritional supplement S-adenosylmethionine was investigated for its role in the synthesis of dopamine and noradrenaline. S-adenosylmethionine appeared to negatively influence cognitive function, increased skin temperature and circulating prolactin concentrations, but no effects on exercise performance were observed.

A presente dissertação procurou determinar as fases do pacing strategy em \"U\" e analisar o desenvolvimento da fadiga neuromuscular e o perfil metabolômico em um teste contrarrelógio de 4 km no ciclismo (4 km CT). No estudo 1, foi proposto dois modelos (visual e matemático) para determinar as três fases do pacing strategy em \"U\" durante um 4 km CT. Foram recrutados 15 ciclistas para realizar dois testes 4 km CT em dias separados. Para o modelo visual, quatro avaliadores experientes analisaram o pacing strategy duas vezes, sete dias de diferença. O modelo matemático foi composto pela média da potência durante a fase 2 (1 até 3 km) mais dois desvios padrões, identificando o ponto de mudança (PM) da fase 2 entre fase 1 (PM1) e 3 (PM2). O PM1 ocorreu em 419 ± 186 e 415 ± 178 m e PM2 ocorreu em 3646 ± 228 e 3809 ± 213 m para o modelo visual e matemático. Não houve diferença entre os modelos para ambos PM (p > 0,05). A reprodutibilidade intra avaliadores no modelo visual para PM1 e PM2 foi ICC >= 0,87 e >= 0,96 (p < 0,05), e entre avaliadores foi ICC >= 0,89 (p < 0,05). Gráficos de Bland-Altman mostraram boa concordância entre modelos, maioria da diferença ficou abaixo de 5%. O estudo 1 sugere que ambos modelos são reprodutíveis e produzem valores similares para determinar as fases do pacing strategy em \"U\". No estudo 2, 11 ciclistas visitaram o laboratório em seis ocasiões, sendo familiarizados três vezes com 4 km CT e técnica de estimulação elétrica no nervo femoral. Nas últimas três visitas, o mesmo pacing strategy da familiarização foi reproduzido, porém foram interrompidos ao final da fase 1 (F1FINAL), fase 2 (F2FINAL) e fase 3 (F3FINAL), randomizado. Antes e logo após o exercício, os ciclistas realizaram a técnica de estimulação elétrica e amostras sanguíneas foram coletadas para determinar o perfil metabolômico. A F1 teve duração de 68 ± 14 s (83,1% acima do ponto de compensação respiratória (PCR), em relação ao tempo total da F1), a F2 durou 287 ± 17 s (24,9% acima do PCR, tempo total da F2) e F3 durou 33 ± 7 s (74,5% acima do PCR, tempo total da F3). Houve apenas efeito principal de tempo para maioria das variáveis neuromusculares (p < 0,05) e não houve efeito principal de condição (p > 0,05). Apenas 5 metabólitos tiveram diferença estatística. Valores menores de 2-oxoisocarporate e dimatilamina para F1FINAL comparado com F2FINAL (p < 0,05). Valores menores de succinato para F1FINAL comparado com F3FINAL (p < 0,05). Asparagina e lactato apresentaram valores menores para F1FINAL em comparação à F2FINAL e F3FINAL (p < 0,05). Esses achados sugerem que, ao longo de um teste 4 km CT, o nível de fadiga neuromuscular é estabelecido logo no início e mantido até o final da tarefa. Não obstante, o perfil metabolômico parece estar associado com metabólitos da via oxidativa e outros marcadores relevantes para o SNC controlar a intensidade do exercício / The present dissertation aimed to determine the distinct phases of \"U\" pacing strategy and the development of neuromuscular fatigue and metabolomic profile during a 4 km cycling time trial (4 km TT). The study 1 developed two models (visual and mathematical) to determine the three different phases of \"U\" pacing strategy during a 4 km TT. Fifteen cyclists were recruited to perform two 4 km TT at different days. For the visual model, four experienced evaluators analysed the pacing twice, seven days apart. The mathematical model was composed by the mean of power output during phase 2 (1 until 3 km) plus two standard deviation, which was the criteria to distinguish the change point (CP) of phase 2 among phase 1 (CP1) and 3 (CP2). CP1 occurred at 419 ± 186 and 415 ± 178 m and CP2 occurred at 3646 ± 228 and 3809 ± 213 m for the visual and mathematical models. There was no difference between models for both CP (p > 0.05). The intra-evaluator reliability of visual model for CP1 and CP2 were ICC >= 0.87 and >= 0.96 (p < 0.05), and the betweenevaluator was ICC >= 0.89 (p < 0.05). The Bland-Altman plots showed great agreement between models, with most values lower than 5% of difference. In conclusion, both models were reliable and produced similar values to distinguish the phases during \"U\" pacing strategy. At study 2, 11 cyclists visited the lab on six occasions, where they were familiarized three times with the 4 km TT and the femoral nerve stimulation technique. On the last three visits, the same pacing strategy from the familiarization was performed, but the cyclists were interrupted at the end of phase 1 (P1END), end of phase 2 (P2END) and end of phase 3 (P3END), randomized. Before and immediately after the exercise, the cyclists performed the stimulation technique and blood samples were collected to determine the metabolimic profile. The P1 had duration of 68 ± 14 s (83.1% above the respiratory compensation point (RCP), in relation with total time of P1), P2 lasted 287 ± 17 s (24.9% above RCP, from total time at P2) and P3 lasted 33 ± 7 s (74.5% above RCP, from total time at P3). Most of neuromuscular variables showed main effect of time (p < 0.05) but no main effect of condition (p > 0.05). Only five metabolites were statistically different among conditions. 2- oxoisocarporate and dimethylamine were lower for P1END compared with P2END. Succinate was lower for P1END compared with P3END. Asparagine and lactate were lower for P1END compared with P2 END and P3END. Those findings suggest that during a 4 km TT, the level of neuromuscular fatigue is established at P1END and maintained until the end of the exercise task. Moreover, the metabolimic profile might be associated with oxidative metabolites and other relevant markers for central nervous system, which may act as feedback to control the exercise intensity

Functional magnetic resonance imaging (fMRI) can be used to track neural activation in the brain during functional activities. The purpose of this study was to investigate brain neural responses to blood flow restricted (BFR) versus control handgrip exercise. Using a randomized crossover design, 25 subjects (12 males, 13 females) completed handgrip exercises during two conditions: BFR vs. control. To familiarize participants with the exercise conditions, one week prior to MRI scanning participants completed each exercise condition once on separate days, with 72 hours between days. The following week fMRI scans were performed at the same time of day, separated by 72 hours. The exercise protocol consisted of five 30-second sets of squeezing a nonmetallic handgrip exerciser (a reported 13.6 kg resistance), doing as many repetitions as possible, with 20-second rest intervals between sets. We saw a significant main effect of exercise condition (BFR versus control) between premotor dorsal (PMd)(F = 5.71, p = 0.022), premotor ventral (PMv)(F = 8.21, p = 0.007), and right ventral striatum (VS_R)(F = 7.36, p = 0.01). When considering anatomical regions of interest, we did not find significant differences between exercise conditions in bilateral S1 (p > 0.82), primary motor cortex (M1)(p > 0.33), supplementary motor area (SMA)(p > 0.66), cerebellum (CB)(p > 0.70), insular cortex (INS)(p > 0.45), anterior cingulate cortex (ACC)(p > 0.24), or thalamus (TH)(p > 0.66). Bilateral ACC (ACC_B), right middle frontal gyrus (MFG_R), and the right primary sensory cortex (S1_R) showed significant linear trends (p = 0.001) over the five exercise sets. Finally, the S1_R, left primary sensory cortex (S1_L), and the right anterior cingulate cortex (ACC_R) showed a main effect of set (p < 0.02). These data demonstrate that acute training with BFR during handgrip exercise results in different neural activation patterns in select areas of the brain, compared to a control. These results show that while completing less work with BFR exercise, subjects can achieve a similar amount of brain neural activation as with a higher-volume exercise. Brain neural activation is important to overall patient health and these findings may be important for prescribing training with BFR in clinical and applied research settings.