Metaplastic neuromodulation via transcranial direct current stimulation has no effect on corticospinal excitability and neuromuscular fatigue.

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation tool with potential for managing neuromuscular fatigue, possibly due to alterations in corticospinal excitability. However, inconsistencies in intra- and inter- individual variability responsiveness to tDCS limit its clinical use. Emerging evidence suggests harnessing homeostatic metaplasticity induced via tDCS may reduce variability and boost its outcomes, yet little is known regarding its influence on neuromuscular fatigue in healthy adults. We explored whether cathodal tDCS (ctDCS) prior to exercise combined with anodal tDCS (atDCS) could augment corticospinal excitability and attenuate neuromuscular fatigue. 15 young healthy adults (6 males, 22 ± 4 years) participated in four pseudo-randomised neuromodulation sessions: sham stimulation prior and during exercise, sham stimulation prior and atDCS during exercise, ctDCS prior and atDCS during exercise, ctDCS prior and sham stimulation during exercise. The exercise constituted an intermittent maximal voluntary contraction (MVC) of the right first dorsal interosseous (FDI) for 10 min. Neuromuscular fatigue was quantified as an attenuation in MVC force, while motor evoked potential (MEP) amplitude provided an assessment of corticospinal excitability. MEP amplitude increased during the fatiguing exercise, whilst across time, force decreased. There were no differences in MEP amplitudes or force between neuromodulation sessions. These outcomes highlight the ambiguity of harnessing metaplasticity to ameliorate neuromuscular fatigue in young healthy individuals.

The interaction between metaplastic neuromodulation and fatigue in multiple sclerosis.

BACKGROUND AND OBJECTIVE: Neuromuscular fatigue contributes to decrements in quality of life in Multiple Sclerosis (MS), yet available treatments demonstrate limited efficacy. Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique which presents promise in managing fatigue, possibly related to its capacity to modulate corticospinal excitability. There is evidence for capitalising on metaplasticity using tDCS for improving outcomes. However, this remains to be explored with fatigue in people with MS (pwMS). We investigated cathodal tDCS (ctDCS) priming on anodal tDCS (atDCS)-induced corticospinal excitability and fatigue modulation in pwMS. METHODS: 15 pwMS and 15 healthy controls completed fatiguing exercise whilst receiving either ctDCS or sham (stDCS) primed atDCS to the motor cortex. We assessed change in contraction force and motor evoked potential (MEP) amplitude across time to represent changes in fatigue and corticospinal excitability. RESULTS AND CONCLUSION: ctDCS primed atDCS induced MEP elevation in healthy participants but not in pwMS, possibly indicating impaired metaplasticity in pwMS. No tDCS-mediated change in the magnitude of fatigue was observed, implying that development of fatigue may not rely on changes in corticospinal excitability. SIGNIFICANCE: These findings expand understanding of tDCS effects in pwMS, highlighting differences that may be relevant in the disease pathophysiology.

Critical considerations of the contribution of the corticomotoneuronal pathway to central fatigue.

Neural drive originating in higher brain areas reaches exercising limb muscles through the corticospinal-motoneuronal pathway, which links the motor cortex and spinal motoneurones. The properties of this pathway have frequently been observed to change during fatiguing exercise in ways that could influence the development of central fatigue (i.e. the progressive reduction in voluntary muscle activation). However, based on differences in motor cortical and motoneuronal excitability between exercise modalities (e.g. single-joint vs. locomotor exercise), there is no characteristic response that allows for a categorical conclusion about the effect of these changes on functional impairments and performance limitations. Despite the lack of uniformity in findings during fatigue, there is strong evidence for marked 'inhibition' of motoneurones as a direct result of voluntary drive. Endogenous forms of neuromodulation, such as via serotonin released from neurones, can directly affect motoneuronal output and central fatigue. Exogenous forms of neuromodulation, such as brain stimulation, may achieve a similar effect, although the evidence is weak. Non-invasive transcranial direct current stimulation can cause transient or long-lasting changes in cortical excitability; however, variable results across studies cast doubt on its claimed capacity to enhance performance. Furthermore, with these studies, it is difficult to establish a cause-and-effect relationship between brain responsiveness and exercise performance. This review briefly summarizes changes in the corticomotoneuronal pathway during various types of exercise, and considers the relevance of these changes for the development of central fatigue, as well as the potential of non-invasive brain stimulation to enhance motor cortical excitability, motoneuronal output and, ultimately, exercise performance.

Motor cortex plasticity is greater in endurance-trained cyclists following acute exercise.

Previous research using transcranial magnetic stimulation (TMS) has shown that plasticity within primary motor cortex (M1) is greater in people who undertake regular exercise, and a single session of aerobic exercise can increase M1 plasticity in untrained participants. This study aimed to examine the effect of an acute bout of exercise on M1 plasticity in endurance-trained (cyclists) and untrained individuals. Fourteen endurance-trained cyclists (mean ± SD; 23 ± 3.8 yr) and 14 untrained individuals (22 ± 1.8 yr) performed two experimental sessions. One session included an acute bout of high-intensity interval training (HIIT) exercise involving stationary cycling, whereas another session involved no-exercise (control). Following exercise (or control), I-wave periodicity repetitive TMS (iTMS) was used (1.5-ms interval, 180 pairs) to induce plasticity within M1. Motor evoked potentials (MEPs) induced by single and paired-pulse TMS over M1 were recorded from a hand muscle at baseline, after HIIT (or control) exercise and after iTMS. Corticospinal and intracortical excitability was not influenced by HIIT exercise in either group (all P > 0.05). There was an increase in MEP amplitude after iTMS, and this was greater after HIIT exercise (compared with control) for all subjects (P < 0.001). However, the magnitude of this response was larger in endurance cyclists compared with the untrained group (P = 0.049). These findings indicate that M1 plasticity induced by iTMS was greater in endurance-trained cyclists following HIIT. Prior history of exercise training is, therefore, an important consideration for understanding factors that contribute to exercise-induced plasticity.NEW & NOTEWORTHY We use a novel form of repetitive transcranial magnetic stimulation to show that motor cortex plasticity is increased after acute exercise and that this effect is bolstered in endurance-trained cyclists. These findings indicate that participation in regular endurance exercise (involving lower limb muscles) has widespread effects on cortical plasticity (assessed in unexercised upper limb muscles) following acute lower-limb cycling exercise. It also highlights that exercise history is an important factor in exercise-induced cortical plasticity.

Submaximal isometric fatiguing exercise of the elbow flexors has no age-related effect on GABAB-mediated inhibition.

Age-related changes in the neuromuscular system can result in differences in fatigability between young and older adults. Previous research has shown that single-joint isometric fatiguing exercise of small muscle results in an age-related compensatory decrease in γ-aminobutyric acid (GABAB)-mediated inhibition. However, this has yet to be established in a larger muscle group. In 15 young (22 ± 4 yr) and 15 older (65 ± 5 yr) adults, long interval cortical inhibition [LICI; 100 ms Interstimulus interval (ISI)] and corticospinal silent period (SP) were measured in the biceps brachii during a 5% electromyography (EMG) contraction using transcranial magnetic stimulation (TMS) before, during, and after a submaximal contraction [30% of maximum voluntary contraction (MVC) force] held intermittently to task failure. Both age groups developed similar magnitude of fatigue (∼24% decline in MVC; P = 0.001) and ∼28% decline in LICI (P = 0.001) post fatiguing exercise. No change in SP duration was observed during and immediately following fatigue (P = 0.909), but ∼6% decrease was seen at recovery in both age groups (P < 0.001). Contrary to previous work in a small muscle, these findings suggest no age-related differences in GABAB-mediated inhibition following single-joint isometric fatiguing exercise of the elbow flexors, indicating that GABAB modulation with aging may be muscle group dependent. Furthermore, variations in SP duration and LICI modulation during and post fatigue in both groups suggest that these measures are likely mediated by divergent mechanisms.NEW & NOTEWORTHY Transcranial magnetic stimulation was used to examine GABAB-mediated inhibition during fatiguing exercise of large muscle group in older adults and young adults. We provide novel evidence to show that when older and young adults are faced with a similar magnitude of elbow flexor muscle fatigue, they have a similar decline in GABAB-mediated inhibition. This suggests that when measured in a large muscle group, older adults maintain the ability to modulate GABAB inhibition during fatiguing exercise.

Motor cortex plasticity and visuomotor skill learning in upper and lower limbs of endurance-trained cyclists.

PURPOSE: Studies with transcranial magnetic stimulation (TMS) show that both acute and long-term exercise can influence TMS-induced plasticity within primary motor cortex (M1). However, it remains unclear how regular exercise influences skill training-induced M1 plasticity and motor skill acquisition. This study aimed to investigate whether skill training-induced plasticity and motor skill learning is modified in endurance-trained cyclists. METHODS: In 16 endurance-trained cyclists (24.4 yrs; 4 female) and 17 sedentary individuals (23.9 yrs; 4 female), TMS was applied in 2 separate sessions: one targeting a hand muscle not directly involved in habitual exercise and one targeting a leg muscle that was regularly trained. Single- and paired-pulse TMS was used to assess M1 and intracortical excitability in both groups before and after learning a sequential visuomotor isometric task performed with the upper (pinch task) and lower (ankle dorsiflexion) limb. RESULTS: Endurance-trained cyclists displayed greater movement times (slower movement) compared with the sedentary group for both upper and lower limbs (all P < 0.05), but there was no difference in visuomotor skill acquisition between groups (P > 0.05). Furthermore, endurance-trained cyclists demonstrated a greater increase in M1 excitability and reduced modulation of intracortical facilitation in resting muscles of upper and lower limbs after visuomotor skill learning (all P < 0.005). CONCLUSION: Under the present experimental conditions, these results indicate that a history of regular cycling exercise heightens skill training-induced M1 plasticity in upper and lower limb muscles, but it does not facilitate visuomotor skill acquisition.

Acute high-intensity exercise and skeletal muscle mitochondrial respiratory function: role of metabolic perturbation.

Recently it was documented that fatiguing, high-intensity exercise resulted in a significant attenuation in maximal skeletal muscle mitochondrial respiratory capacity, potentially due to the intramuscular metabolic perturbation elicited by such intense exercise. With the utilization of intrathecal fentanyl to attenuate afferent feedback from group III/IV muscle afferents, permitting increased muscle activation and greater intramuscular metabolic disturbance, this study aimed to better elucidate the role of metabolic perturbation on mitochondrial respiratory function. Eight young, healthy males performed high-intensity cycle exercise in control (CTRL) and fentanyl-treated (FENT) conditions. Liquid chromatography-mass spectrometry and high-resolution respirometry were used to assess metabolites and mitochondrial respiratory function, respectively, pre- and postexercise in muscle biopsies from the vastus lateralis. Compared with CTRL, FENT yielded a significantly greater exercise-induced metabolic perturbation (PCr: -67% vs. -82%, Pi: 353% vs. 534%, pH: -0.22 vs. -0.31, lactate: 820% vs. 1,160%). Somewhat surprisingly, despite this greater metabolic perturbation in FENT compared with CTRL, with the only exception of respiratory control ratio (RCR) (-3% and -36%) for which the impact of FENT was significantly greater, the degree of attenuated mitochondrial respiratory capacity postexercise was not different between CTRL and FENT, respectively, as assessed by maximal respiratory flux through complex I (-15% and -33%), complex II (-36% and -23%), complex I + II (-31% and -20%), and state 3CI+CII control ratio (-24% and -39%). Although a basement effect cannot be ruled out, this failure of an augmented metabolic perturbation to extensively further attenuate mitochondrial function questions the direct role of high-intensity exercise-induced metabolite accumulation in this postexercise response.

Remote muscle priming anodal transcranial direct current stimulation attenuates short interval intracortical inhibition and increases time to task failure of a constant workload cycling exercise.

Anodal transcranial direct current stimulation (atDCS), a non-invasive neuromodulatory technique has been shown to increase the excitability of targeted brain area and influence endurance exercise performance. However, the effect of atDCS applied on an unexercised muscle motor cortex (M1) representation on GABAA-mediated intracortical inhibition and endurance exercise performance remains unknown. In two separate sessions, twelve subjects performed fatigue cycling exercise (80% peak power output) sustained to task failure in a double-blinded design, following either ten minutes of bicephalic anodal tDCS (atDCS) or sham applied on a non-exercised hand muscle M1 representation. Short interval intracortical inhibition (SICI) was measured at baseline, post neuromodulation and post-exercise using paired-pulse transcranial magnetic stimulation (TMS) in a resting hand muscle. There was a greater decrease in SICI (P < 0.05) post fatigue cycling with atDCS priming compared to sham. Time to task failure (TTF) was significantly increased following atDCS compared to sham (P < 0.05). These findings suggest that atDCS applied over the non-exercised muscle M1 representation can augment cycling exercise performance; and although this outcome may be mediated via a multitude of mechanisms, a decrease in the global excitability of GABAA inhibitory interneurons may be a possible contributing factor.

Ascorbate attenuates cycling exercise-induced neuromuscular fatigue but fails to improve exertional dyspnea and exercise tolerance in COPD.

We examined the effect of intravenous ascorbate (VitC) administration on exercise-induced redox balance, inflammation, exertional dyspnea, neuromuscular fatigue, and exercise tolerance in patients with chronic obstructive pulmonary disease (COPD). Eight COPD patients completed constant-load cycling (∼80% of peak power output, 83 ± 10 W) to task failure after intravenous VitC (2 g) or saline (placebo, PL) infusion. All participants repeated the shorter of the two exercise trials (isotime) with the other infusate. Quadriceps fatigue was determined by pre- to postexercise changes in quadriceps twitch torque (ΔQtw, electrical femoral nerve stimulation). Corticospinal excitability before, during, and after exercise was assessed by changes in motor evoked potentials triggered by transcranial magnetic stimulation. VitC increased superoxide dismutase (marker for endogenous antioxidant capacity) by 129% and mitigated C-reactive protein (marker for inflammation) in the plasma during exercise but failed to alter the exercise-induced increase in lipid peroxidation (malondialdehyde) and free radicals [electron paramagnetic resonance (EPR)-spectroscopy]. Although VitC did, indeed, decrease neuromuscular fatigue (ΔQtw: PL -29 ± 5%, VitC -23 ± 6%, P < 0.05), there was no impact on corticospinal excitability and time to task failure (∼8 min, P = 0.8). Interestingly, in terms of pulmonary limitations to exercise, VitC had no effect on perceived exertional dyspnea (∼8.5/10) and its determinants, including oxygen saturation ([Formula: see text]) (∼92%) and respiratory muscle work (∼650 cmH2O·s·min-1) (P > 0.3). Thus, although VitC facilitated indicators for antioxidant capacity, diminished inflammatory markers, and improved neuromuscular fatigue resistance, it failed to improve exertional dyspnea and cycling exercise tolerance in patients with COPD. As dyspnea is recognized to limit exercise tolerance in COPD, the otherwise beneficial effects of VitC may have been impacted by this unaltered sensation.NEW & NOTEWORTHY We investigated the effect of intravenous vitamin C on redox balance, exertional dyspnea, neuromuscular fatigue, and exercise tolerance in chronic obstructive pulmonary disease (COPD) patients. Acute vitamin C administration increased superoxide dismutase (marker of antioxidant capacity) and attenuated fatigue development but failed to improve exertional dyspnea and exercise tolerance. These findings suggest that a compromised redox balance plays a critical role in the development of fatigue in COPD but also highlight the significance of exertional dyspnea as an important symptom limiting the patients' exercise tolerance.

Single joint fatiguing exercise decreases long but not short-interval intracortical inhibition in older adults.

Ageing is accompanied by neuromuscular changes which may alter fatigue in older adults. These changes may include changes in corticospinal excitatory and inhibitory processes. Previous research has suggested that single joint fatiguing exercise decreases short-(SICI) and long-(LICI) interval intracortical inhibition in young adults. However, this is yet to be established in older adults. In 19 young (23 ± 4 years) and 18 older (69 ± 5 years) adults, SICI (2 ms interstimulus interval; ISI) and LICI (100 ms ISI) were measured in a resting first dorsal interosseous (FDI) muscle using transcranial magnetic stimulation (TMS) before and after a 15 min sustained submaximal contraction at 25% of their maximum EMG. Subsequent ten 2-min contractions held at 25% EMG were also performed to sustain fatigue for a total of 30 min, while SICI and LICI were taken immediately after each contraction. There was no change in SICI post-fatiguing exercise compared to baseline in both young and older adults (P = 0.4). Although there was no change in LICI post-fatiguing exercise in younger adults (P = 1.0), LICI was attenuated in older adults immediately post-fatiguing exercise and remained attenuated post-fatigue (PF)1 and PF2 (P < 0.05). Contrary to previous studies, the lack of change in SICI and LICI in young adults following a sustained submaximal EMG contraction suggests that GABA modulation may be dependent on the type of fatiguing task performed. The reduction in LICI in older adults post-fatiguing exercise suggests an age-related decrease in GABAB-mediated activity with sustained submaximal fatiguing exercise.

TMS coil orientation and muscle activation influence lower limb intracortical excitability.

INTRODUCTION: Previous research with transcranial magnetic stimulation (TMS) indicates that coil orientation (TMS current direction) and muscle activation state (rest or active) modify corticospinal and intracortical excitability of upper limb muscles. However, the extent to which these factors influence corticospinal and intracortical excitability of lower limb muscles is unknown. This study aimed to examine how variations in coil orientation and muscle activation affect corticospinal and intracortical excitability of tibialis anterior (TA), a lower leg muscle. METHODS: In 21 young (21.6 ± 3.3 years, 11 female) adults, TMS was administered to the motor cortical representation of TA in posterior-anterior (PA) and mediolateral (ML) orientations at rest and during muscle activation. Single-pulse TMS measures of motor evoked potential amplitude, in addition to resting and active motor thresholds, were used to index corticospinal excitability, whereas paired-pulse TMS measures of short-interval intracortical inhibition (SICI) and facilitation (SICF), and long-interval intracortical inhibition (LICI), were used to assess excitability of intracortical circuits. RESULTS: For single-pulse TMS, motor thresholds and test TMS intensity were lower for ML stimulation (all P < 0.05). In a resting muscle, ML TMS produced greater SICI (P < 0.001) and less SICF (both P < 0.05) when compared with PA TMS. In contrast, ML TMS in an active muscle resulted in reduced SICI but increased SICF (both P ≤ 0.001) when compared with PA TMS. CONCLUSION: TMS coil orientation and muscle activation influence measurements of intracortical excitability recorded in the tibialis anterior, and are therefore important considerations in TMS studies of lower limb muscles.

Freely Chosen Cadence During Cycling Attenuates Intracortical Inhibition and Increases Intracortical Facilitation Compared to a Similar Fixed Cadence.

In contrast to other rhythmic tasks such as running, the preferred movement rate in cycling does not minimize energy consumption. It is possible that neurophysiological mechanisms contribute to the choice of cadence, however this phenomenon is not well understood. Eleven participants cycled at a fixed workload of 125 W and different cadences including a freely chosen cadence (FCC, ∼72), and fixed cadences of 70, 80, 90 and 100 revolutions per minute (rpm) during which transcranial magnetic stimulation (TMS) was used to measure short interval intracortical inhibition (SICI) and intracortical facilitation (ICF). There was a significant increase in SICI at 70 (P = 0.004), 80 (P = 0.008) and 100 rpm (P = 0.041) compared to FCC. ICF was significantly reduced at 70 rpm compared to FCC (P = 0.04). Inhibition-excitation ratio (SICI divided by ICF) declined (P = 0.014) with an increase in cadence. The results demonstrate that SICI is attenuated during FCC compared to fixed cadences. The outcomes suggest that the attenuation of intracortical inhibition and augmentation of ICF may be a contributing factor for FCC.

Preconditioning cathodal transcranial direct current stimulation facilitates the neuroplastic effect of subsequent anodal transcranial direct current stimulation applied during cycling in young adults.

The study aimed to examine the effect of a pre-conditioning cathodal transcranial direct current stimulation (ctDCS) before subsequent anodal-tDCS (atDCS) was applied during low workload cycling exercise on the corticospinal responses in young healthy individuals. Eleven young subjects participated in two sessions receiving either conditioning ctDCS or sham stimulation, followed by atDCS while cycling (i.e. ctDCS-atDCS, sham-atDCS) at 1.2 times their body weight (84 ±â€¯20 W) in a counterbalanced double-blind design. Corticospinal excitability was measured with motor evoked potentials (MEPs) elicited via transcranial magnetic stimulation with the intensity set to produce an MEP amplitude of 1 mV in a resting hand muscle at baseline (PRE), following pre-conditioning tDCS (POST-COND) and post atDCS combined with cycling exercise (POST-TEST). There was a significant interaction between time and intervention (P < 0.01) on MEPs. MEPs increased from PRE (1.0 ±â€¯0.06 mV) to POST-TEST (1.3 ±â€¯0.06 mV) during ctDCS-atDCS (P < 0.001) but did not change significantly across time during sham-atDCS (P > 0.7). Furthermore, MEPs were higher in ctDCS-atDCS compared to sham-atDCS (both P < 0.01) at POST-COND (ctDCS-atDCS: 1.1 ±â€¯0.06 mV, sham-atDCS: 1.0 ±â€¯0.06 mV) and POST-TEST (ctDCS-atDCS: 1.3 ±â€¯0.06 mV, sham-atDCS: 1.0 ±â€¯0.06 mV). These outcomes demonstrate that pre-conditioning cathodal tDCS can enhance subsequent corticospinal excitability changes induced by anodal tDCS applied in combination with cycling exercise. The findings have implications for the application of tDCS in combination with cycling exercise in rehabilitation and sporting contexts.

Older Adults Differentially Modulate Transcranial Magnetic Stimulation-Electroencephalography Measures of Cortical Inhibition during Maximal Single-joint Exercise.

The effects of muscle fatigue are known to be altered in older adults, and age-related changes in the brain are likely to be a contributing factor. However, the neural mechanisms underlying these changes are not known. The aim of the current study was to use transcranial magnetic stimulation combined with electroencephalography (TMS-EEG) to investigate age-related changes in cortical excitability with muscle fatigue. In 23 young (mean age ±â€¯SD: 22 ±â€¯2 years) and 17 older (mean age ±â€¯SD: 68.3 ±â€¯5.6 years) adults, single-pulse TMS-EEG was applied before, during and after the performance of fatiguing, intermittent isometric abduction of the index finger. Motor-evoked potential (MEP) measures of cortical excitability were increased during (estimated mean difference, 123.3%; P < 0.0001) and after (estimated mean difference, 117.5%; P = 0.001) fatigue and this was not different between groups (P > 0.5). For TMS-EEG, the amplitude of the P30 and P180 potentials were unaffected by fatigue in older participants (P > 0.05). In contrast, the amplitude of the N45 potential in older adults was significantly reduced both during (positive cluster: mean voltage difference = 0.7 µV, P < 0.005; negative cluster: mean voltage difference = 0.9 µV, P < 0.0005) and after (mean voltage difference = 0.5 µV, P < 0.005) fatiguing exercise, whereas this response was absent in young participants. These results suggest that performance of maximal intermittent isometric exercise in old but not young adults is associated with modulation of cortical inhibition likely mediated by activation of gamma-aminobutyric acid type A receptors.

Exercise Pressor Reflex Contributes to the Cardiovascular Abnormalities Characterizing: Hypertensive Humans During Exercise.

We investigated the impact of hypertension on circulatory responses to exercise and the role of the exercise pressor reflex in determining the cardiovascular abnormalities characterizing patients with hypertension. After a 7-day drug washout, 8 hypertensive (mean arterial pressure [MAP] 130±4 mm Hg; 65±3 years) and 8 normotensive (MAP 117±2 mm Hg; 65±2 years) individuals performed single-leg knee-extensor exercise (7 W, 15 W, 50%, 80%-Wpeak) under control conditions and with lumbar intrathecal fentanyl impairing feedback from µ-opioid receptor-sensitive leg muscle afferents. Femoral artery blood flow (QL), MAP (femoral artery), leg vascular conductance, and changes in cardiac output were continuously measured. While the increase in MAP from rest to control exercise was significantly greater in hypertension compared with normotension, the exercise-induced increase in cardiac output was comparable between groups, and QL and leg vascular conductance responses were ≈18% and ≈32% lower in the hypertensive patients (P<0.05). The blockade-induced decreases in MAP were significantly larger during exercise in hypertensive (≈11 mm Hg) compared with normotensive (≈6 mm Hg). Afferent blockade attenuated the central hemodynamic response to exercise similarly in both groups resulting in a ≈15% lower cardiac output at each workload. With no effect in normotensive, afferent blockade significantly raised the peripheral hemodynamic response to exercise in hypertensive, resulting in ≈14% and ≈23% higher QL and leg vascular conductance during exercise. Finally, QL and MAP during fentanyl-exercise in hypertensive were comparable to that of normotensive under control conditions (P>0.2). These findings suggest that exercise pressor reflex abnormalities largely account for the exaggerated MAP response and the impaired peripheral hemodynamics during exercise in hypertension.

Intermittent single-joint fatiguing exercise reduces TMS-EEG measures of cortical inhibition.

Fatiguing intermittent single-joint exercise causes an increase in corticospinal excitability and a decrease in intracortical inhibition when measured with peripherally recorded motor evoked potentials (MEPs) after transcranial magnetic stimulation (TMS). Combined TMS and electroencephalography (TMS-EEG) allows for more direct recording of cortical responses through the TMS-evoked potential (TEP). The aim of this study was to investigate the changes in the excitatory and inhibitory components of the TEP during fatiguing single-joint exercise. Twenty-three young (22 ± 2 yr) healthy subjects performed intermittent 30-s maximum voluntary contractions of the right first dorsal interosseous muscle, followed by a 30-s relaxation period repeated for a total of 15 min. Six single-pulse TMSs and one peripheral nerve stimulation (PNS) to evoke maximal M wave (Mmax) were applied during each relaxation period. A total of 90 TMS pulses and 5 PNSs were applied before and after fatiguing exercise to record MEP and TEP. The amplitude of the MEP (normalized to Mmax) increased during fatiguing exercise ( P < 0.001). There were no changes in local and global P30, N45, and P180 of TEPs during the development of intermittent single-joint exercise-induced fatigue. Global analysis, however, revealed a decrease in N100 peak of the TEP during fatiguing exercise compared with before fatiguing exercise ( P = 0.02). The decrease in N100 suggests a fatigue-related decrease in global intracortical GABAB-mediated inhibition. The increase in corticospinal excitability typically observed during single-joint fatiguing exercise may be mediated by a global decrease in intracortical inhibition. NEW & NOTEWORTHY Fatiguing intermittent single-joint exercise causes an increase in corticospinal excitability and a decrease in intracortical inhibition when measured with transcranial magnetic stimulation (TMS)-evoked potentials from the muscle. The present study provides new and direct cortical evidence, using TMS-EEG to demonstrate that during single-joint fatiguing exercise there is a global decrease in intracortical GABAB-mediated inhibition.

Acute High-Intensity Exercise Impairs Skeletal Muscle Respiratory Capacity.

PURPOSE: The effect of an acute bout of exercise, especially high-intensity exercise, on the function of mitochondrial respiratory complexes is not well understood, with potential implications for both the healthy population and patients undergoing exercise-based rehabilitation. Therefore, this study sought to comprehensively examine respiratory flux through the different complexes of the electron transport chain in skeletal muscle mitochondria before and immediately after high-intensity aerobic exercise. METHODS: Muscle biopsies of the vastus lateralis were obtained at baseline and immediately after a 5-km time trial performed on a cycle ergometer. Mitochondrial respiratory flux through the complexes of the electron transport chain was measured in permeabilized skeletal muscle fibers by high-resolution respirometry. RESULTS: Complex I + II state 3 (state 3CI + CII) respiration, a measure of oxidative phosphorylation capacity, was diminished immediately after the exercise (pre, 27 ± 3 ρm·mg·s; post, 17 ± 2 ρm·mg·s; P < 0.05). This decreased oxidative phosphorylation capacity was predominantly the consequence of attenuated complex II-driven state 3 (state 3CII) respiration (pre, 17 ± 1 ρm·mg·s; post, 9 ± 2 ρm·mg·s; P < 0.05). Although complex I-driven state 3 (3CI) respiration was also lower (pre, 20 ± 2 ρm·mg·s; post, 14 ± 4 ρm·mg·s), this did not reach statistical significance (P = 0.27). In contrast, citrate synthase activity, proton leak (state 2 respiration), and complex IV capacity were not significantly altered immediately after the exercise. CONCLUSIONS: These findings reveal that acute high-intensity aerobic exercise significantly inhibits skeletal muscle state 3CII and oxidative phosphorylation capacity. This, likely transient, mitochondrial defect might amplify the exercise-induced development of fatigue and play an important role in initiating exercise-induced mitochondrial adaptations.

Fatigue-related group III/IV muscle afferent feedback facilitates intracortical inhibition during locomotor exercise.

KEY POINTS: This study investigated the influence of group III/IV muscle afferents on corticospinal excitability during cycling exercise and focused on GABAB neuron-mediated inhibition as a potential underlying mechanism. The study provides novel evidence to demonstrate that group III/IV muscle afferent feedback facilitates inhibitory intracortical neurons during whole body exercise. Firing of these interneurons probably contributes to the development of central fatigue during physical activity. ABSTRACT: We investigated the influence of group III/IV muscle afferents in determining corticospinal excitability during cycling exercise and focused on GABAB neuron-mediated inhibition as a potential underlying mechanism. Both under control conditions (CTRL) and with lumbar intrathecal fentanyl (FENT) impairing feedback from group III/IV leg muscle afferents, subjects (n = 11) cycled at a comparable vastus-lateralis EMG signal (∼0.26 mV) before (PRE; 100 W) and immediately after (POST; 90 ± 2 W) fatiguing constant-load cycling exercise (80% Wpeak; 221 ± 10 W; ∼8 min). During, PRE and POST cycling, single and paired-pulse (100 ms interstimulus interval) transcranial magnetic stimulations (TMS) were applied to elicit unconditioned and conditioned motor-evoked potentials (MEPs), respectively. To distinguish between cortical and spinal contributions to the MEPs, cervicomedullary stimulations (CMS) were used to elicit unconditioned (CMS only) and conditioned (TMS+CMS, 100 ms interval) cervicomedullary motor-evoked potentials (CMEPs). While unconditioned MEPs were unchanged from PRE to POST in CTRL, unconditioned CMEPs increased significantly, resulting in a decrease in unconditioned MEP/CMEP (P < 0.05). This paralleled a reduction in conditioned MEP (P < 0.05) and no change in conditioned CMEP. During FENT, unconditioned and conditioned MEPs and CMEPs were similar and comparable during PRE and POST (P > 0.2). These findings reveal that feedback from group III/IV muscle afferents innervating locomotor muscle decreases the excitability of the motor cortex during fatiguing cycling exercise. This impairment is, at least in part, determined by the facilitating effect of these sensory neurons on inhibitory GABAB intracortical interneurons.

Impact of age on the development of fatigue during large and small muscle mass exercise.

To examine the impact of aging on neuromuscular fatigue following cycling (CYC; large active muscle mass) and single-leg knee-extension (KE; small active muscle mass) exercise, 8 young (25 ± 4 years) and older (72 ± 6 years) participants performed CYC and KE to task failure at a given relative intensity (80% of peak power output). The young also matched CYC and KE workload and duration of the old (iso-work comparison). Peripheral and central fatigue were quantified via pre-/postexercise decreases in quadriceps twitch torque (∆Qtw, electrical femoral nerve stimulation) and voluntary activation (∆VA). Although young performed 77% and 33% more work during CYC and KE, respectively, time to task failure in both modalities was similar to the old (~9.5 min; P > 0.2). The resulting ΔQtw was also similar between groups (CYC ~40%, KE ~55%; P > 0.3); however, ∆VA was, in both modalities, approximately double in the young (CYC ~6%, KE ~9%; P < 0.05). While causing substantial peripheral and central fatigue in both exercise modalities in the old, ∆Qtw in the iso-work comparison was not significant (CYC; P = 0.2), or ~50% lower (KE; P < 0.05) in the young, with no central fatigue in either modality ( P > 0.4). Based on iso-work comparisons, healthy aging impairs fatigue resistance during aerobic exercise. Furthermore, comparisons of fatigue following exercise at a given relative intensity mask the age-related difference observed following exercise performed at the same workload. Finally, although active muscle mass has little influence on the age-related difference in the rate of fatigue at a given relative intensity, it substantially impacts the comparison during exercise at a given absolute intensity.