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This study presents the novel finding that 4-wk resistance training (RT) focused specifically on the lower limbs can reduce exertional dyspnea during constant-load cycling, improve exercise tolerance, and reduce intrinsic fatigability of the quadriceps in individuals with COPD.

Electrically evoked contractions provide insight into intrinsic neuromuscular fatigability and also represent a valuable technique to maintain muscle mass in a clinical setting. To appropriately investigate intrinsic fatigability and design optimal stimulation protocols, it would seem to be crucial to stimulate the muscle at a frequency equivalent to the mean motor unit discharge rate expected at the target force level.

This historical review summarizes the major advances – particularly from the last 50 years – in transcutaneous motor-level electrical stimulation, which can be used either as a tool to investigate neuromuscular function and its determinants (electrical stimulation for testing; EST) or as a therapeutic/training modality to improve neuromuscular and physical function (neuromuscular electrical stimulation; NMES). We focus on some of the most important applications of electrical stimulation in research and clinical settings, such as the investigation of acute changes, chronic adaptations and pathological alterations of neuromuscular function with EST, as well as the enhancement, preservation and restoration of muscle strength and mass with NMES treatment programs in various populations. For both EST and NMES, several major advances converge around understanding and optimizing motor unit recruitment during electrically-evoked contractions, also taking into account the influence of stimulation site (e.g., muscle belly vs nerve trunk) and type (e.g., pulse duration, frequency, and intensity). This information is equally important both in the context of mechanistic research of neuromuscular function as well as for clinicians who believe that improvements in neuromuscular function are required to provide health-related benefits to their patients.

Regional brain iron accumulation is observed in many neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, and is associated with cognitive decline. We explored associations between age, cognition and iron content in grey matter regions and hippocampal subfields in 380 participants of the Aberdeen children of the 1950s cohort and their first-generation relatives (aged 26-72 years). Participants underwent cognitive assessment at the time of MRI scanning. Quantitative susceptibility mapping of these MRI data was used to assess iron content in grey matter regions and in hippocampal subfields. Principle component analysis was performed on cognitive test scores to create a general cognition score. Spline analysis was used with the Akaike information criterion to determine if order 1, 2 or 3 natural splines were optimal for assessing non-linear relationships between regional iron and age. Multivariate linear models were used to assess associations between regional iron and cognition. Higher iron correlated with older age in the left putamen across all ages and in the right putamen of only participants over 58. Whereas a decrease in iron with older age was observed in the right thalamus and left pallidum across all ages. Right amygdala iron levels were associated with poorer general cognition scores and poorer immediate recall scores. Iron was not associated with any measures of cognitive performance in other regions of interest. Our results suggest that, whilst iron in some regions was associated with cognitive performance, there is an overall lack of association between regional iron content and cognitive ability in cognitively healthy individuals.

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.

Quantifying prolonged low-frequency force depression (PLFFD) with the gold-standard 1-s trains presents challenges, so paired pulses have been used. Owing to greater impairment of high-frequency doublet than tetanic torque, paired pulses underestimate PLFFD. This study aimed to approximate the minimum number of high-frequency pulses needed to avoid such underestimation and assess the feasibility of modeling PLFFD from a limited number of experimental pulses. In 13 participants, a 1-s 10-Hz train and 100-Hz trains with 2, 4, 7, 12, 15, 25, 50, or 100 pulses were evoked before and after (15 min, 2, 4, and 7 days) eccentric exercise of the dorsiflexors. With ≤12 pulses, impairment of 100-Hz torque was greater than the 1-s train (

Sleep deprivation (SD) is prevalent and impairs motor function; however, little is known about its effect on perceived and performance fatigability, especially in females. To examine the effects of 24 h of SD on these attributes of fatigue, nine females completed a 20-min isometric, sustained elbow flexion contraction, followed by 10 min of recovery. The superimposed twitch (SIT) elicited via transcranial magnetic stimulation (TMS) assessed supraspinal drive. Biceps brachii electromyographic data indicated neural excitability in response to stimulation over the motor cortex (motor evoked potential; MEP), corticospinal tract (cervicomedullary motor evoked potential; CMEP), and brachial plexus (maximal M-wave; Mmax). MEPs and CMEPs were recorded during a TMS-induced silent period. At baseline, ratings of perceived effort (RPE; 2.9 vs. 1.6) and fatigue (RPF; 6.9 vs. 2.9), were higher for SD than control. Across the 20-min contraction, RPE increased from 2.2 to 7.6, SIT and MEP/CMEP increased by 284 and 474%, respectively, whereas maximal voluntary isometric contraction (MVC) torque and CMEP/Mmax decreased by 26 and 57%, respectively. No differences were found across conditions for MVC, SIT, Mmax, CMEP/Mmax, or MEP/CMEP prior to, during, and after the fatiguing task. During recovery, RPE (4.9 vs. 3.4), RPF (7.6 vs. 2.8), and perception of task difficulty (5.5 vs. 4.5) were greater for SD than control. Acute SD does not appear to alter performance fatigability development and subsequent recovery; however, it increases perceptions of fatigue, effort, and task difficulty. Thus, the disconnect between perceived and actual neuromuscular capacity following a sustained, submaximal isometric task is exacerbated by SD.

Adult aging is associated with a myriad of changes within the neuromuscular system, leading to reductions in contractile function of old adults. One of the consequences of these age-related neuromuscular adaptations is altered performance fatigability, which can limit the ability of old adults to perform activities of daily living. Whereas age-related fatigability during isometric tasks has been well characterized, considerably less is known about fatigability of old adults during dynamic tasks involving movement about a joint, which provides a more functionally relevant task compared with static contractions. This review provides a comprehensive summary of age-related fatigability during dynamic contractions, where the importance of task specificity is highlighted with a brief discussion of the potential mechanisms responsible for differences in fatigability between young and old adults. The angular velocity of the task is critical for evaluating age-related fatigability, as tasks that constrain angular velocity (i.e., isokinetic) produce equivocal age-related differences in fatigability, whereas tasks involving unconstrained velocity (i.e., isotonic-like) consistently induce greater fatigability for old compared with young adults. These unconstrained velocity tasks, which are more closely associated with natural movements, offer an excellent model to uncover the underlying age-related mechanisms of increased fatigability. Future work evaluating the mechanisms of increased age-related fatigability during dynamic tasks should be evaluated using contraction modes that are specific to the task (i.e., dynamic), rather than isometric, particularly for the assessment of spinal and supra spinal components. Advancing our understanding of age-related fatigability is likely to yield novel insights and approaches for improving mobility limitations in old adults.

The purpose of this study was to assess how severe acute hypoxia alters the neural mechanisms of muscle activation across a wide range of torque output in a fatigued muscle. Torque and electromyography responses to transcranial and motor nerve stimulation were collected from 10 participants (27 years ± 5 years, 1 female) following repeated performance of a sustained maximal voluntary contraction that reduced torque to 60% of the pre-fatigue peak torque. Contractions were performed after 2 h of hypoxic exposure and during a sham intervention. For hypoxia, peripheral blood oxygen saturation was titrated to 80% over a 15-min period and remained at 80% for 2 h. Maximal voluntary torque, electromyography root mean square, voluntary activation and corticospinal excitability (motor evoked potential area) and inhibition (silent period duration) were then assessed at 100%, 90%, 80%, 70%, 50% and 25% of the target force corresponding to the fatigued maximal voluntary contraction. No hypoxia-related effects were identified for voluntary activation elicited during motor nerve stimulation. However, during measurements elicited at the level of the motor cortex, voluntary activation was reduced at each torque output considered (P = .002, η

Transcutaneous electrical stimulation (TES) is used to activate muscles when volitional capacity is impaired but potential benefits are limited by rapid force loss (fatigue). Most TES fatigue protocols employ constant-frequency trains, with stimuli at a fixed interstimulus interval (ISI); however, a brief ISI between the first two pulses (variable-frequency train, VFT) to maximize the catchlike property of muscle can attenuate fatigue development. The purpose of this study was to investigate if a VFT that simulates intrinsic variability of voluntary motor unit discharge rates would also mitigate fatigue, owing to the sensitivity of muscle to acute activation history.On two visits, 24 healthy adults (25.3 ± 3.7 years; 12 females) received 3 min of intermittent TES to the quadriceps of the dominant leg. Trains of eight pulses at 10 Hz were delivered with a constant (100 ms) or variable ISI (80-120 ms). Contractile impulse, rate of force development (RFD), and rate of relaxation (RFR) were determined for each tetanus RESULTS: During fatigue and recovery, contractile impulse did not differ between protocols (p ≥ 0.796) and sexes (p ≥ 0.493), with values of 77 ± 17% control at task end and 125 ± 19% control 2 min later. RFD and RFR also showed no effect of the protocol (p ≥ 0.310) or participant sex (p ≥ 0.119). Both measures slowed (38 ± 23% and 33 ± 22%, respectively) but dissociated during recovery as RFD remained 16 ± 18% below control at 5 min, whereas RFR recovered to control by 30 s (101 ± 22%).Contrary to expectations, the VFT protocol did not attenuate fatigue development, which suggests no benefit to mimicking the inherent variability of motor unit discharge rates.

PURPOSE To investigate possible sex-related differences in group III/IV muscle afferent feedback with isometric fatigue, we aimed to assess the effect of a sustained submaximal elbow extensor contraction on motoneuronal excitability (cervicomedullary motor evoked potential [CMEP]) and voluntary activation (VA). METHODS Twenty-four participants (12 females) performed a 15-min contraction at the level of EMG activity recorded at 15% of maximal torque. Each minute, CMEP were elicited by cervicomedullary stimulation with and without conditioning transcranial magnetic stimulation (TMS) delivered 100 ms earlier. Unconditioned and conditioned motor evoked potentials (MEP) in response to TMS were also recorded to assess motor cortical excitability. CMEP and MEP were normalized for changes in downstream excitability and expressed as percentage of their prefatigue (control) values. Postfatigue, VA was calculated from superimposed and resting tetani evoked by stimulation over triceps brachii. RESULTS Males were twice as strong as females, but the sexes did not differ for any variable during the fatigue protocol. On a 0-10 scale, RPE increased from ~2.5 to 9. The unconditioned CMEP did not change, whereas the conditioned CMEP was reduced by ~50%. By contrast, the unconditioned and conditioned MEP increased to ~200% and ~320% of the control values, respectively. At task termination, maximal torque was reduced ~40%, and VA was ~80%, down from a prefatigue value of ~96%. CONCLUSIONS Results support the scant published data on the elbow extensors and indicate no sex-related differences for isometric fatigue of this muscle group. The motoneuronal and VA data suggest that metabolite buildup and group III/IV muscle afferent activity were similar for females and males.

Blood flow occlusion (BFO) has been used to study the influence of group III/IV muscle afferents after fatiguing exercise, but it is unknown how BFO-induced activity of these afferents affects motor cortical and motoneuronal excitability during low-intensity exercise. Therefore, the purpose of this study was to assess the acute effect of BFO on peripheral [maximal M wave (Mmax)], spinal [cervicomedullary motor evoked potential (CMEP) normalized to Mmax], and motor cortical [motor evoked potential (MEP) normalized to CMEP] excitability. Nine healthy men completed a sustained isometric contraction of the elbow flexors at 20% of maximal force under three conditions: 1) contractile failure with BFO, 2) a time-matched trial without restriction [free flow (FFiso)], and 3) contractile failure with free flow (FFfail). Time to failure for BFO (and FFiso) were ~80% shorter than that for FFfail ( P < 0.05). For FFfail and FFiso, Mmax area decreased ~17% and ~7%, respectively ( P < 0.05), with no change during BFO. CMEP/Mmax area increased ~226% and ~80% during BFO and FFfail, respectively ( P < 0.05), with no change during FFiso ( P > 0.05). The increase in normalized CMEP area was greater for BFO and FFfail compared with FFiso and for BFO compared with FFfail. MEP/CMEP area was not different among the protocols ( P > 0.05) and increased ~64% with time ( P < 0.05). It is likely that group III/IV muscle afferent feedback to the spinal cord modulates the large increase in motoneuronal excitability for the BFO compared with FFfail and FFiso protocols. NEW & NOTEWORTHY We have observed how blood flow occlusion modulates motor cortical, spinal, and peripheral excitability during and immediately after a sustained low-intensity isometric elbow flexion contraction to failure. We conclude that blood flow occlusion causes a greater and more rapid increase in motoneuronal excitability.

Ascent to high altitude is accompanied by a reduction in partial pressure of inspired oxygen, which leads to interconnected adjustments within the neuromuscular system. This review describes the unique challenge that such an environment poses to neuromuscular fatigability (peripheral, central and supraspinal) for individuals who normally reside near to sea level (SL) (1000 m; ie, lowlanders) and for native highlanders, who represent the manifestation of high altitude-related heritable adaptations across millennia. Firstly, the effect of acute exposure to high altitude-related hypoxia on neuromuscular fatigability will be examined. Under these conditions, both supraspinal and peripheral fatigability are increased compared with SL. The specific mechanisms contributing to impaired performance are dependent on the exercise paradigm and amount of muscle mass involved. Next, the effect of chronic exposure to high altitude (ie, acclimatization of ~7-28 days) will be considered. With acclimatization, supraspinal fatigability is restored to SL values, regardless of the amount of muscle mass involved, whereas peripheral fatigability remains greater than SL except when exercise involves a small amount of muscle mass (eg, knee extensors). Indeed, when whole-body exercise is involved, peripheral fatigability is not different to acute high-altitude exposure, due to competing positive (haematological and muscle metabolic) and negative (respiratory-mediated) effects of acclimatization on neuromuscular performance. In the final section, we consider evolutionary adaptations of native highlanders (primarily Himalayans of Tibet and Nepal) that may account for their superior performance at altitude and lesser degree of neuromuscular fatigability compared with acclimatized lowlanders, for both single-joint and whole-body exercise.

We investigated the effect of high-altitude acclimatization on peripheral fatigue compared with sea level and acute hypoxia.At sea level (350 m), acute hypoxia (environmental chamber), and chronic hypoxia (5050 m, 5-9 d) (partial pressure of inspired oxygen = 140, 74 and 76 mm Hg, respectively), 12 participants (11 in chronic hypoxia) had the quadriceps of their dominant leg fatigued by three bouts of 75 intermittent electrically evoked contractions (12 pulses at 15 Hz, 1.6 s between train onsets, and 15 s between bouts). The initial peak force was ~30% of maximal voluntary force. Recovery was assessed by single trains at 1, 2, and 3 min postprotocol. Tissue oxygenation of rectus femoris was recorded by near-infrared spectroscopy.At the end of the fatigue protocol, the impairments of peak force and peak rates of force development and relaxation were greater (all P0.05) in acute hypoxia (~51%, 53%, and 64%, respectively) than sea level (~43%, 43%, and 52%) and chronic hypoxia (~38%, 35%, and 48%). Peak force and rate of force development recovered faster (P0.05) in chronic hypoxia (pooled data for 1-3 min: ~84% and 74% baseline, respectively) compared with sea level (~73% and 63% baseline) and acute hypoxia (~70% and 55% baseline). Tissue oxygenation did not differ among conditions for fatigue or recovery (P0.05).Muscle adaptations occurring with chronic hypoxia, independent of other adaptations, positively influence muscle contractility during and after repeated contractions at high altitude.

Purpose: In volleyball, jump execution is critical for the match outcome. Game-play-related neuromuscular impairments may manifest as decreased jump height (JH) or increased jump total duration, both of which are pivotal for performance. To investigate changes in JH and kinetics with game play, the authors conducted a prospective exploratory analysis using minimal-effect testing (MET) and equivalence testing with the 2 one-sided tests procedure, univariate, and bivariate functional principal component analysis, respectively. Methods: Twelve male varsity athletes completed 3-set matches on 2 consecutive days. Countermovement jumps were performed on a force platform immediately prematch and postmatch on days 1 and 2 and once on days 3 and 4. Results: Across sessions, JH was equivalent (P P > .227). After match 2, MET indicated that relative force at zero velocity (P = .036) decreased, while braking duration (P = .040) and time to peak force (P = .048) increased compared with baseline. With the first and second functional principal components, these alterations, together with decreased relative braking rate of force development (P = .092), were already evident after match 1. On day 4, MET indicated that relative peak force (P = .049), relative force at zero velocity (P = .023), and relative braking rate of force development (P = .021) decreased, whereas braking duration (P = .025) increased from baseline. Conclusions: Impairments in jump kinetics were evident from variables related to the countermovement-jump braking phase, while JH was equivalent. In addition to these experimental findings, the present research provides information for the choice of sample size and smallest effect size of interest when using MET and 1- and 2-dimensional analyses for countermovement-jump height and kinetics.

Key points Acute hypoxia has been shown to impair voluntary activation of muscle and alter the excitability of the corticospinal motor pathway during exercise. However, little is known about how hypoxia alters the recovery of the motor system after performing fatiguing exercise. Here we assessed hypoxia-related responses of motor pathways during both active contractions, and the recovery from active contractions, with transcranial magnetic stimulation and motor point stimulation of the biceps brachii. Fatiguing exercise caused reductions in voluntary activation, which was exacerbated during recovery from a 10 min sustained elbow flexion in a hypoxia environment. These results suggest that reductions in blood oxygen concentration impair the ability of motor pathways in the central nervous system to recover from fatiguing exercise, which is likely due to hypoxia-induced mechanisms that reduce output of the motor cortex. Abstract The purpose of this study was to determine how severe acute hypoxia alters neural mechanisms during, and following, a sustained fatiguing contraction. Fifteen participants (25 ± 3.2 years, 6 female) were exposed to a sham condition and a hypoxia condition where they performed a 10-min elbow flexor contraction at 20% of maximal torque. For hypoxia, peripheral blood oxygen saturation (SpO2 ) was titrated to 80% over a 15-min period and maintained for 2 hr. Maximal voluntary contraction (MVC) torque, EMG root mean square (EMGRMS ), voluntary activation, rating of perceived muscle fatigue, and corticospinal excitability (motor evoked potential) and inhibition (silent period duration) were then assessed before, during, and for 6 min after the fatiguing contraction. No hypoxia-related effects were identified for neuromuscular variables during the fatigue task. However, for recovery, voluntary activation assessed by motor point stimulation of biceps brachii was lower for hypoxia than sham at 4 min (sham: 89% ± 7%; hypoxia: 80% ± 12%; P = 0.023) and 6 min (sham: 90% ± 7%; hypoxia: 78% ± 11%; P = 0.040). Similarly, voluntary activation (P = 0.01) and motor evoked potential area (P = 0.002) in response to transcranial magnetic stimulation of the motor cortex were 10% and 11% lower during recovery for hypoxia compared to sham, respectively. Although an SpO2 of 80% did not affect neural activity during the fatiguing task, motor cortical output and corticospinal excitability were reduced during recovery in the hypoxic environment. This was likely due to hypoxia-related mechanisms involving supraspinal motor circuits. This article is protected by copyright. All rights reserved.

Unaccustomed eccentric (ECC) exercise induces muscle fatigue as well as damage and initiates a protective response to minimize impairments from a subsequent bout (i.e., repeated bout effect; RBE). It is uncertain if the sexes differ for neuromuscular responses to ECC exercise and the ensuing RBE. Twenty-six young adults (13 females) performed 2 bouts (4 weeks apart) of 200 ECC maximal voluntary contractions (MVCs) of the dorsiflexors. Isometric (ISO) MVC torque and the ratio of ISO torque in response to low- versus high-frequency stimulation (10:100 Hz) were compared before and after (2–10 min and 2, 4, and 7 days) exercise. The decline in ECC and ISO MVC torque and the 10:100 Hz ratio following bout 1 did not differ between sexes (P > 0.05), with reductions from baseline of 31.5% ± 12.3%, 24.1% ± 15.4%, and 51.3% ± 12.2%, respectively. After bout 2, the 10:100 Hz ratio declined less (45.0% ± 12.4% from baseline) and ISO MVC torque recovered sooner compared with bout 1 but no differences between sexes were evident for the magnitude of the RBE (P > 0.05). These data suggest that fatigability with ECC exercise does not differ for the sexes and adaptations that mitigate impairments to calcium handling are independent of sex. Novelty: One bout of 200 maximal eccentric dorsiflexor contractions caused equivalent muscle fatigue and damage for females and males. The repeated bout effect observed after a second bout 4 weeks later also had no sex-related differences. Prolonged low-frequency force depression is promoted as an indirect measure of muscle damage in humans.

New findings What is the central question of this study? How does acute hypoxia alter central and peripheral fatigue during brief and sustained maximal voluntary muscle contractions? What is the main finding and its importance? Perception of fatigue during muscle contractions was increased progressively for 2 h after hypoxic exposure. However, an increase in motor cortex excitability and a decrease in voluntary activation of skeletal muscle were observed across the entire protocol when performing brief (3 s) maximal contractions. These adaptations were abolished if the brief contraction was held for a duration of 20 s, which was presumably attributable to a successful redistribution of blood to overcome the reduced oxygen content. Abstract Few studies have examined the time course of changes in the motor system after acute exposure to hypoxia. Thus, the purpose of this study was to examine how acute hypoxia affects corticospinal excitability, voluntary activation (VA) and the perception of fatigue during brief (3 s) and sustained (20 s) maximal voluntary contractions (MVCs). Fourteen healthy individuals (23 ± 2.2 years of age; four female) were exposed to hypoxia and sham conditions. During hypoxia, peripheral blood oxygen saturation was titrated over a 15 min period and remained at 80% during testing. Corticospinal excitability and VA were assessed before titration (Pre), 0, 1 and 2 h after. At each time point, the brief and sustained elbow flexion MVCs were performed. Motor evoked potentials (MEPs) were obtained using transcranial magnetic stimulation. Superimposed and resting twitches were obtained from motor point stimulation of biceps brachii to calculate the level of VA, and ratings of perceived fatigue were obtained with a modified CR-10 Borg scale. A condition-by-time interaction was detected for the CR-10 Borg scale, whereby perception of fatigue increased progressively throughout the hypoxia protocol. However, main effects of MEP area and VA indicated that corticospinal excitability increased, and VA of the biceps brachii decreased, throughout the hypoxia protocol. Given that these changes in MEP area and VA were seen only when performing the brief MVCs (and not during the sustained MVCs), performing longer contractions might overcome reduced oxygen content by redirecting blood flow to active areas of the motor system.

Ongoing low-frequency activity in the brain has been shown to indicate an inhibitory neural state; however, the effects of this low-frequency activity on event-related neural processes associated with movement preparation, including movement-related cortical potentials (MRCPs) or more specifically, the motor potential (MP), and event-related desynchronization (ERD) have not been assessed. Using data from 48 participants, the current study examined how ongoing mu and beta frequency activity at rest relates to the MP and mu and beta ERD during real or imagined movement of the fingers. Resting state EEG activity was collected for 1 min, prior to the real and imagined finger movement trials. 20 real and 20 imagined movement trials were collected for each hand. Resting beta activity correlated with MP amplitude during movement trials for both the right (r(47) = -0.304, p = 0.035) and left (r(47) = -0.468, p0.001) hands, whereas resting mu correlated with MP amplitude during motor imagery trials of both the right (r(47) = -0.289, p = 0.046) and left (r(47) = -0.330, p = 0.020) hands. Ongoing mu and beta activity was not significantly correlated with mu or beta ERD for both the movement and imagery trials. A connection between low-frequency activity and MP could inform biofeedback procedures that promote a reduction of this activity, ultimately allowing for easier identification of the intent to move.

Data are scant on sex-related differences for electrically evoked contractions, which assess intrinsic contractile properties while limiting spinal and supraspinal adaptations to mitigate fatigue. Furthermore, the few studies that exist use stimulus frequencies considerably higher than the natural motor unit discharge rate for the target force. The purpose of this study was to compare force loss to electrically evoked contractions at a physiological stimulus frequency among young females (n = 12), young males (n = 12), old females (n = 11), and old males (n = 11). The quadriceps of the dominant leg were fatigued by 3 min of intermittent transcutaneous muscle belly stimulation (15 Hz stimulus train to initially evoke 25% of maximal voluntary force). Impairment of tetanic contractile impulse (area under the curve) did not differ between sexes for young or old adults or between age groups, with a pooled value of 55.2% ± 12.4% control at the end of fatigue. These data contrast with previous findings at 30 Hz, when the quadriceps of females had greater fatigue resistance than males for young and old adults. The present results highlight the impact stimulus frequency has on intrinsic fatigability of muscle; the findings have implications for future fatigue paradigms and treatment approaches when utilizing electrical stimulation for rehabilitation. Novelty Fatigue was not different between sexes with a stimulation frequency comparable to discharge rates during voluntary contractions. These results highlight that stimulus frequency not only influences fatigue development but also between-group differences.

Movement complexity is known to increase reaction time (RT). More recently, transcranial magnetic stimulation (TMS) of the motor cortex has revealed that movement complexity can alter corticospinal excitability. However, the impact of a sequential addition of movement components on corticospinal excitability during the preparatory phase of a simple RT task is unknown. Thus, the purpose of this study was to examine how motor evoked potentials (MEPs) in the premotor period were affected by the complexity of a movement in a simple RT paradigm. Participants (n = 12) completed ballistic movements with their dominant arm, in which they directed a robotic handle to one, two or three targets (32 trials per condition). TMS was delivered prior to movement at 0, 70, 80 or 90% of each participant's mean premotor RT, at the stimulator intensity which yielded a triceps brachii MEP of ~ 10% the maximal M-wave. As expected, premotor RT slowed with increasing task complexity. Although background electromyographic activity (EMG) of the triceps brachii during the preparation phase did not differ among conditions, MEP amplitude increased with movement complexity (i.e., MEPs were greater for the 2- and 3-movement conditions, compared to the 1-movement condition at 80% of premotor RT). We propose the lengthened RTs could be due in part to less suppression of particular motor circuits, while other circuitry is responsible for the increased MEPs. This study demonstrates that, prior to movement, corticospinal excitability increases as a consequence of movement complexity.

Following active lengthening, steady-state isometric (ISO) torque is greater than a purely ISO contraction at the same muscle length, this is referred to as residual torque enhancement (rTE). A phenomenon of rTE is activation reduction, characterized by reduced electromyography (EMG) amplitude for a given torque output. We hypothesized that lower motor unit discharge rates would contribute to activation reduction and lessening torque steadiness. Ten young male subjects performed ISO dorsiflexion contractions at 10 and 20% of maximal voluntary contraction (MVC) torque. During rTE trials, the muscle was activated at 10° of plantar flexion, then the ankle was rotated to the ISO position at 40°. Fine wire electrodes recorded motor unit (MU)-discharge rates and variability from the tibialis anterior. Surface EMG quantified activation reduction, and steadiness was determined as the coefficient of variation of torque. The activation reduction was 44 and 24% at 10 and 20% MVC, respectively (P < 0.05). Fewer MUs were recorded in the rTE than ISO condition at 10% (~47%) and 20% (~36%) MVC (P < 0.05). Discharge rates were 19 and 26% lower in the rTE compared with the ISO condition for 10 and 20% MVC, respectively (P < 0.05), with no difference in variability between conditions (P > 0.05). Steadiness was ~22 and 18% lower for the rTE than ISO condition at 10 and 20% MVC (P < 0.05). Our findings indicate that activation reduction may be attributed to lower MU discharge rate and fewer detectable MUs and that this theoretically contributes to a reduction in steadiness in the rTE condition. NEW & NOTEWORTHY Our findings indicate that lower electromyographic activity during the torque enhanced condition following active lengthening compared with a purely isometric contraction arises from fewer active motor units and a lower discharge rate of those that are active. We used an acute condition of increased torque capacity to induce a decrease in net output of the motor neuron pool during a submaximal task to demonstrate, in humans, the impact of motor unit activity on torque steadiness.

Sleep deprivation is commonplace and impairs memory, inhibition, cognitive flexibility and attention. However, little is known about the neurophysiological impact of sleep deprivation in the context of go/no-go (GNG) task performance and emotion processing. To address this knowledge gap, 12 females performed two computerized GNG tasks (shapes; emotional facial expressions) and an object hit and avoid (OHA) task after a night of typical sleep and 24 h without sleep. Electroencephalographic (EEG) recordings were taken during a 3-minute eyes-open resting period as well as during GNG task performance. Resting EEG power in the theta band was 33% higher for the sleep-deprived than control condition (p 0.05), whereas alpha activity was unchanged. When sleep deprived, participants had ~6% slower response times (go trials) and made ~7% more total errors during GNG tasks (p 0.05). Reaction time and overall accuracy were ~25% and ~9% worse for the emotional compared to shape GNG task (p 0.05), respectively, which suggests interference of emotion processing on task performance. Smaller differences in amplitude between go and no-go trials for the N2 and both the N2 and P3 event-related potential components were found during sleep deprivation for the emotional and shape GNG tasks, respectively (p 0.05). No changes to the N170 component were found. Lastly, participants hit more distractors during the OHA task when sleep deprived (p 0.05). Altogether, these results indicate sleep deprivation slows neural processing and impairs inhibitory task performance, possibly due to a more bottom-up, stimulus-driven approach to inhibiting motor responses.

KEY POINTS The reduced oxygen tension of high altitude compromises performance in lowlanders. In this environment, Sherpa display superior performance, but little is known on this issue. Sherpa present unique genotypic and phenotypic characteristics at the muscular level, which may enhance resistance to peripheral fatigue at high altitude compared to lowlanders. We studied the impact of gradual ascent and exposure to high altitude (5050 m) on peripheral fatigue in age-matched lowlanders and Sherpa, using intermittent electrically-evoked contractions of the knee extensors. Peripheral fatigue (force loss) was lower in Sherpa during the first part of the protocol. Post-protocol, the rate of force development and contractile impulse recovered faster in Sherpa than in lowlanders. At any time, indices of muscle oxygenation were not different between groups. Muscle contractile properties in Sherpa, independent of muscle oxygenation, were less perturbed by non-volitional fatigue. Hence, elements within the contractile machinery contribute to the superior physical performance of Sherpa at high altitude. ABSTRACT Altitude-related acclimatisation is characterised by marked muscular adaptations. Lowlanders and Sherpa differ in their muscular genotypic and phenotypic characteristics, which may influence peripheral fatigability at altitude. After gradual ascent to 5050 m, 12 lowlanders and 10 age-matched Sherpa (32 ± 10 vs. 31 ± 11 years, respectively) underwent three bouts (separated by 15 s rest) of 75 intermittent electrically-evoked contractions (12 pulses at 15 Hz, 1.6 s between train onsets) of the dominant leg quadriceps, at the intensity which initially evoked 30% of maximal voluntary force. Trains were also delivered at minutes 1, 2 and 3 after the protocol to measure recovery. Tissue oxygenation index (TOI) and total haemoglobin (tHb) were quantified by a near-infrared spectroscopy probe secured over rectus femoris. Superficial femoral artery blood flow was recorded using ultrasonography, and delivery of oxygen was estimated (eDO2 ). At the end of bout 1, peak force was greater in Sherpa than in lowlanders (91.5% vs. 84.5% baseline, respectively; P < 0.05). Peak rate of force development (pRFD), the first 200 ms of the contractile impulse (CI200 ), and half-relaxation time (HRT) recovered faster in Sherpa than in lowlanders (percentage of baseline at 1 min: pRFD: 89% vs. 74%; CI200 : 91% vs. 80%; HRT: 113% vs. 123%, respectively; P < 0.05). Vascular measures were pooled for lowlanders and Sherpa as they did not differ during fatigue or recovery (P < 0.05). Mid bout 3, TOI was decreased (90% baseline) whereas tHb was increased (109% baseline). After bout 3, eDO2 was markedly increased (1266% baseline). The skeletal muscle of Sherpa seemingly favours repeated force production at altitude for similar oxygen delivery compared to lowlanders.

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 0.2). 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.

Human biological aging from maturity to senescence is associated with a gradual loss of muscle mass and neuromuscular function. It is not until very old age (>80 years) however, that these changes often manifest into functional impairments. A driving factor underlying the age-related loss of muscle mass and function is the reduction in the number and quality of motor units (MUs). A MU consists of a single motoneuron, located either in the spinal cord or the brain stem, and all of the muscle fibres it innervates via its peripheral axon. Throughout the adult lifespan, MUs are slowly, but progressively lost. The compensatory process of collateral reinnervation attempts to recapture orphaned muscle fibres following the death of a motoneuron. Whereas this process helps mitigate loss of muscle mass during the latter decades of adult aging, the neuromuscular system has fewer and larger MUs, which have lower quality connections between the axon terminal and innervated muscle fibres. Whether this process of MU death and degradation can be attenuated with habitual physical activity has been a challenging question of great interest. This review focuses on age-related alterations of the human neuromuscular system, with an emphasis on the MU, and presents findings on the potential protective effects of lifelong physical activity. Although there is some discrepancy across studies of masters athletes, if one considers all experimental limitations as well as the available literature in animals, there is compelling evidence of a protective effect of chronic physical training on human MUs. Our tenet is that high-levels of physical activity can mitigate the natural trajectory of loss of quantity and quality of MUs in old age.

KEY POINTS Acute exposure and acclimatization to hypoxia are associated with an impairment and partial recovery, respectively, of the capability of the central nervous system to drive muscles during prolonged efforts. Motoneurones play a vital role in muscle contraction and in fatigue, although the effect of hypoxia on motoneurone excitability during exercise has not been assessed in humans. We studied the impact of fatigue on motoneurone excitability in normoxia, acute and chronic exposure (5050 m) to hypoxia. Performance was worse in acute hypoxia but recovered to the normoxic standard in chronic hypoxia, in parallel with an increased excitability of the motoneurones compared to acute exposure to hypoxia. These findings reveal that prolonged hypoxia causes a heightened motoneurone responsiveness during fatiguing exercise; such an adaptation might favour the restoration of performance where low pressures of oxygen are chronically present. ABSTRACT The fatigue-induced failure of the motor cortex to drive muscles maximally increases in acute hypoxia (AH) compared to normoxia (N) but improves with acclimatization (chronic hypoxia; CH). Despite their importance to muscle output, it is unknown how locomotor motoneurones in humans are affected by hypoxia and acclimatization. Eleven participants performed 16 min of submaximal [25% maximal torque (maximal voluntary contraction, MVC)] intermittent isometric elbow flexions in N, AH (environmental chamber) and CH (7-14 days at 5050 m) (PI O2 = 140, 74 and 76 mmHg, respectively). For each minute of the fatigue protocol, motoneurone responsiveness was measured with cervicomedullary stimulation delivered 100 ms after transcranial magnetic stimulation (TMS) used to transiently silence voluntary drive. Every 2 min, cortical voluntary activation (cVA) was measured with TMS. After the task, MVC torque declined more in AH (∼20%) than N and CH (∼11% and 14%, respectively, P

This study compared the effects of fatigue on corticospinal responsiveness in the upper- and lower-limb muscles of the same participants. Seven healthy males performed a 2-min maximal voluntary isometric contraction of the elbow flexors or knee extensors on four separate days. Electromyographic responses were elicited by nerve stimulation (maximal M-wave) in all sessions and by transcranial magnetic stimulation (motor-evoked potential; silent period) and spinal tract stimulation (cervicomedullary or thoracic motor-evoked potentials; silent period) in one session each per limb. During sustained maximal voluntary contractions, motor-evoked potential area normalised to M-waves increased from baseline in biceps brachii (155 ± 55%) and rectus femoris (151 ± 44%) (both p ≤ 0.045). At the end of maximal voluntary contractions, spinal tract motor-evoked potential area normalised to M-waves was smaller than baseline in biceps brachii (74 ± 23%; p = 0.012) but not rectus femoris (108 ± 40%; p = 0.999). The ratio of motor-evoked potential to spinal tract-evoked potential areas increased dramatically from 90 to 115 s in biceps brachii (p = 0.001) but not in rectus femoris (p = 0.999). Silent period durations increased similarly in both muscles (p ≤ 0.008) after transcranial and spinal stimulation. Sustained maximal contractions elicit different neurophysiological adjustments in upper- and lower-limb muscles. Specifically, motoneuronal excitability was reduced in biceps brachii, but not in rectus femoris, and this reduction required greater compensatory adjustments from the motor cortex. Therefore, changes in cortical and spinal excitability during sustained maximal exercise are likely specific to the muscle performing the task.

Elbow flexor force steadiness is less with the forearm pronated (PRO) compared with neutral (NEU) or supinated (SUP) and may relate to neural excitability. Although not tested in a force steadiness paradigm, lower spinal and cortical excitability was observed separately for biceps brachii in PRO, possibly dependent on contractile status at the time of assessment. This study aimed to investigate position-dependent changes in force steadiness as well as spinal and cortical excitability at a variety of contraction intensities. Thirteen males (26 ± 7 yr; means ± SD) performed three blocks (PRO, NEU, and SUP) of 24 brief (~6 s) isometric elbow flexor contractions (5, 10, 25 or 50% of maximal force). During each contraction, transcranial magnetic stimulation or transmastoid stimulation was delivered to elicit a motor-evoked potential (MEP) or cervicomedullary motor-evoked potential (CMEP), respectively. Force steadiness was lower in PRO compared with NEU and SUP ( P ≤ 0.001), with no difference between NEU and SUP. Similarly, spinal excitability (CMEP/maximal M wave) was lower in PRO than NEU (25 and 50% maximal force; P ≤ 0.010) and SUP (all force levels; P ≤ 0.004), with no difference between NEU and SUP. Cortical excitability (MEP/CMEP) did not change with forearm position ( P = 0.055); however, a priori post hoc testing for position showed excitability was 39.8 ± 38.3% lower for PRO than NEU at 25% maximal force ( P = 0.006). The data suggest that contraction intensity influences the effect of forearm position on neural excitability and that reduced spinal and, to a lesser extent, cortical excitability could contribute to lower force steadiness in PRO compared with NEU and SUP. NEW & NOTEWORTHY To address conflicting reports about the effect of forearm position on spinal and cortical excitability of the elbow flexors, we examine the influence of contraction intensity. For the first time, excitability data are considered in a force steadiness context. Motoneuronal excitability is lowest in pronation and this disparity increases with contraction intensity. Cortical excitability exhibits a similar pattern from 5 to 25% of maximal force. Lower corticospinal excitability likely contributes to relatively poor force steadiness in pronation.

Prolonged low-frequency force depression (PLFFD) after damaging eccentric exercise may last for several days. Historically, PLFFD has been calculated from the tetanic force responses to trains of supramaximal stimuli. More recently, for methodological reasons, stimulation has been reduced to two pulses. However, it is unknown whether doublet responses provide a valid measure of PLFFD in the days after eccentric exercise. In 12 participants, doublets and tetani were elicited at 10 and 100 Hz before and after (2, 3, 5 min, 48 and 96 h) 200 eccentric maximal voluntary contractions of the dorsiflexors. Doublet and tetanic torque responses at 10 Hz were similarly depressed throughout recovery ( P > 0.05; e.g., 2 min: 58.9 ± 12.8% vs. 57.1 ± 14.5% baseline; 96 h: 85.6 ± 11.04% vs. 85.1 ± 10.8% baseline). At 100 Hz, doublet torque was impaired more than tetanic torque at all time points ( P < 0.05; e.g., 2 min: 70.5 ± 14.2% vs. 88.1 ± 11.7% baseline; 96 h: 83.0 ± 14.2% vs. 98.7 ± 9.5% baseline). As a result, the postfatigue reduction of the 10 Hz-to-100 Hz ratio (PLFFD) was markedly greater for tetani than for doublets ( P < 0.05; e.g., 2 min: 64.3 ± 15.1% vs. 83.0 ± 5.8% baseline). In addition, the doublet ratio recovered by 48 h (99.2 ± 5.0% baseline), whereas the tetanic ratio was still impaired at 96 h (88.2 ± 9.7% baseline). Our results indicate that doublets are not a valid measure of PLFFD in the minutes and days after eccentric exercise. If study design favors the use of paired stimuli, it should be acknowledged that the true magnitude and duration of PLFFD are likely underestimated.NEW & NOTEWORTHY Prolonged low-frequency force depression (PLFFD) will result from damaging exercise and may last for several days. After 200 eccentric maximal dorsiflexor contractions, we compared the gold-standard measure of PLFFD (calculated using trains of supramaximal stimulation) to the value obtained from an alternative technique that is becoming increasingly common (paired supramaximal stimuli). Doublets underestimated the magnitude and duration of PLFFD compared with tetani, so caution must be used when reporting PLFFD derived from paired stimuli.

Mental fatigue is commonplace but there is limited understanding of the neural underpinnings of its development, the time course of its recovery, and its impact on motor function. Hence, this study used neural (electroencephalography) and motor measures to investigate the development and recovery of mental fatigue. Twenty participants performed a 60-min N-back task, with neural activity compared within the task. Additionally, pre-task neural and motor measures were compared to assessments beginning at 0, 30 and 60 min post-task. Alpha power increased during the task and was greater than baseline at 30 and 60 min post-task. Motor skills were impaired at ∼10–17 min post-task but recovered at ∼40–47 min. Using a unique combination of neural and motor measures, our results suggest that attentiveness and, possibly, selectiveness in inhibiting irrelevant information are impaired after an acute mentally-fatiguing task. Notably, recovery time differed for neural and motor measures.

New Findings What is the central question of this study? Do group III and IV muscle afferents act at the spinal or cortical level to affect the ability of the central nervous system to drive quadriceps muscles during fatiguing exercise? What is the main finding and its importance? The excitability of the motoneurone pool of vastus lateralis was unchanged by feedback from group III and IV muscle afferents. In contrast, feedback from these afferents may contribute to inhibition at the cortex. However, the excitability of the corticospinal pathway was not directly affected by feedback from these afferents. These findings are important for understanding neural processes during fatiguing exercise. In upper limb muscles, changes in afferent feedback, motoneurone excitability, and motor cortical output can contribute to failure of the central nervous system to recruit muscles fully during fatigue. It is not known whether similar changes occur with fatigue of muscles in the lower limb. We assessed the corticospinal pathway to vastus lateralis during fatiguing sustained maximal voluntary contractions (MVCs) of the knee extensors and during firing of fatigue-sensitive group III/IV muscle afferents maintained by postexercise ischaemia after fatiguing MVCs of the knee extensors and, separately, the flexors. In two experiments, subjects (n = 9) performed brief knee extensor MVCs before and after 2-min sustained MVCs of the knee extensors (experiment 1) or knee flexors (experiment 2). During MVCs, motor evoked potentials (MEPs) were elicited by transcranial magnetic stimulation over the motor cortex and thoracic motor evoked potentials (TMEPs) by electrical stimulation over the thoracic spine. During the 2-min extensor contraction, the size of vastus lateralis MEPs normalized to the maximal M-wave increased (P

Based on H-reflex data, spinal mechanisms are proposed to be responsible for the first 50–80 ms of the transcranial magnetic stimulation (TMS)-induced silent period. As several methodological issues can compromise H-reflex validity as a measure of motoneuron excitability, this study used transmastoid stimulation to elicit cervicomedullary motor evoked potentials (CMEPs) during the silent period. Eleven subjects made 1–3 visits which involved 32 or 44 brief (~3 s) isometric elbow flexor contractions at 25 % of maximal torque. During each contraction, transmastoid stimulation was delivered in isolation to elicit an unconditioned CMEP and at interstimulus intervals (ISIs) ranging from 50 to 150 ms after TMS to elicit a conditioned CMEP. Stimulus intensities for TMS and transmastoid stimulation were set to elicit a silent period of ~200 ms and an unconditioned CMEP of 15, 50, or 85 % of the maximal compound muscle action potential (M max), respectively. At all ISIs and intensities of transmastoid stimulation, the conditioned CMEP was significantly smaller than the unconditioned CMEP (p

This study determined whether short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) change during a sustained submaximal isometric contraction. On 2 days, 12 participants (6 men, 6 women) performed brief (7-s) elbow flexor contractions before and after a 10-min fatiguing contraction; all contractions were performed at the level of integrated electromyographic activity (EMG) which produced 25 % maximal unfatigued torque. During the brief 7-s and 10-min submaximal contractions, single (test) and paired (conditioning–test) transcranial magnetic stimuli were applied over the motor cortex (5 s apart) to elicit motor-evoked potentials (MEPs) in biceps brachii. SICI and ICF were elicited on separate days, with a conditioning–test interstimulus interval of 2.5 and 15 ms, respectively. On both days, integrated EMG remained constant while torque fell during the sustained contraction by ~51.5 % from control contractions, perceived effort increased threefold, and MVC declined by 21–22 %. For SICI, the conditioned MEP during control contractions (74.1 ± 2.5 % of unconditioned MEP) increased (less inhibition) during the sustained contraction (last 2.5 min: 86.0 ± 5.1 %; P

Acetazolamide, a carbonic anhydrase (CA) inhibitor used clinically and to prevent acute mountain sickness, worsens skeletal muscle fatigue in animals and humans. In animals, methazolamide, a methylated analog of acetazolamide and an equally potent CA inhibitor, reportedly exacerbates fatigue less than acetazolamide. Accordingly, we sought to determine, in humans, if methazolamide would attenuate diaphragm and dorsiflexor fatigue compared with acetazolamide. Healthy men (dorsiflexor: n = 12; diaphragm: n = 7) performed fatiguing exercise on three occasions, after ingesting acetazolamide (250 mg three times a day) and then in random order, methazolamide (100 mg twice a day) or placebo for 48 h. For both muscles, subjects exercised at a fixed intensity until exhaustion on acetazolamide, with subsequent iso-time and -workload trials. Diaphragm exercise was performed using a threshold-loading device, while dorsiflexor exercise was isometric. Neuromuscular function was determined pre- and postexercise by potentiated transdiaphragmatic twitch pressure and dorsiflexor torque in response to stimulation of the phrenic and fibular nerve, respectively. Diaphragm contractility 3–10 min postexercise was impaired more for acetazolamide than methazolamide or placebo (82 ± 10, 87 ± 9, and 91 ± 8% of pre-exercise value; P < 0.05). Similarly, dorsiflexor fatigue was greater for acetazolamide than methazolamide (mean twitch torque of 61 ± 11 vs. 57 ± 13% of baseline, P < 0.05). In normoxia, methazolamide leads to less neuromuscular fatigue than acetazolamide, indicating a possible benefit for clinical use or in the prophylaxis of acute mountain sickness. NEW & NOTEWORTHY Acetazolamide, a carbonic anhydrase inhibitor, may worsen diaphragm and locomotor muscle fatigue after exercise; whereas, in animals, methazolamide does not impair diaphragm function. Compared with both methazolamide and the placebo, acetazolamide significantly compromised dorsiflexor function at rest and after exhaustive exercise. Similarly, diaphragm function was most compromised on acetazolamide followed by methazolamide and placebo. Methazolamide may be preferable over acetazolamide for clinical use and altitude illness prophylaxis to avoid skeletal muscle dysfunction.

Torque depression (TD) is the reduction in steady-state isometric torque following active muscle shortening when compared to an isometric reference contraction at the same muscle length and activation level. Central nervous system excitability differs in the TD state. While torque production about a joint is influenced by both agonist and antagonist muscle activation, investigations of corticospinal excitability have focused on agonist muscle groups. Hence, it is unknown how the TD state affects spinal and supraspinal excitability of an antagonist muscle. Eight participants (~ 24y, three female) performed 14 submaximal dorsiflexion contractions at the intensity needed to maintain a level of integrated electromyographic activity in the soleus equivalent to 15% of that recorded during a maximum plantar flexion contraction. The seven contractions of the TD protocol included a 2 s isometric phase at an ankle angle of 140°, a 1 s shortening phase at 40°/s, and a 7 s isometric phase at an angle of 100°. The seven isometric reference contractions were performed at an ankle angle of 100° for 10 s. Motor evoked potentials (MEPs), cervicomedullary motor evoked potentials (CMEPs), and maximal M-waves (Mmax) were recorded from the soleus in both conditions. In the TD compared to isometric reference state, a 13% reduction in dorsiflexor torque was accompanied by 10% lower spinal excitability (normalized CMEP amplitude; CMEP/Mmax), and 17% greater supraspinal excitability (normalized MEP amplitude; MEP/CMEP) for the soleus muscle. These findings demonstrate a neuromechanical coupling following active muscle shortening and indicate that the underlying mechanisms of TD influence antagonist activation during voluntary force production.

Purpose At high altitude, Lowlanders exhibit exacerbated fatigue and impaired performance. Conversely, Sherpa (native Highlanders) are known for their outstanding performance at altitude. Presently, there are no reports comparing neuromuscular fatigue and its etiology between Lowlanders and Sherpa at altitude. Methods At 5050 m, nine age-matched Lowlanders and Sherpa (31 ± 10 vs 30 ± 12 yr, respectively) completed a 4-min sustained isometric elbow flexion at 25% maximal voluntary contraction (MVC) torque. Mid-minute, stimuli were applied to the motor cortex and brachial plexus to elicit a motor-evoked potential and maximal compound muscle action potential (Mmax), respectively. Supraspinal fatigue was assessed as the reduction in cortical voluntary activation (cVA) from prefatigue to postfatigue. Cerebral hemoglobin concentrations and tissue oxygenation index (TOI) were measured over the prefrontal cortex by near-infrared spectroscopy. Results Prefatigue, MVC torque, and cVA were significantly greater for Lowlanders than Sherpa (79.5 ± 3.6 vs 50.1 ± 11.3 N·m, and 95.4% ± 2.7% vs 88.2% ± 6.6%, respectively). With fatigue, MVC torque and cVA declined similarly for both groups (~24%-26% and ~5%-7%, respectively). During the task, motor-evoked potential area increased more and sooner for Lowlanders (1.5 min) than Sherpa (3.5 min). The Mmax area was lower than baseline throughout fatigue for Lowlanders but unchanged for Sherpa. TOI increased earlier for Lowlanders (2 min) than Sherpa (4 min). Total hemoglobin increased only for Lowlanders (2 min). Mmax was lower, whereas TOI and total hemoglobin were higher for Lowlanders than Sherpa during the second half of the protocol. Conclusions Although neither MVC torque loss nor development of supraspinal fatigue was different between groups, neural-evoked responses and cerebral oxygenation indices were less perturbed in Sherpa. This represents an advantage for maintenance of homeostasis, presumably due to bequeathed genotype and long-term altitude adaptations.

Background Following active muscle lengthening, there is an increase in steady-state isometric force as compared with a purely isometric contraction at the same muscle length and level of activation. This fundamental property of skeletal muscle is known as residual force enhancement (RFE). While the basic mechanisms contributing to this increase in steady-state isometric force have been well documented, changes in central nervous system (CNS) excitability for submaximal contractions during RFE are unclear. The purpose of this study was to investigate spinal and supraspinal excitability in the RFE isometric steady-state following active lengthening of the ankle dorsiflexor muscles. Methods A total of 11 male participants (20–28 years) performed dorsiflexions at a constant level of electromyographic activity (40% of maximum). Half of the contractions were purely isometric (8 s at an ankle angle of 130°), and the other half were during the RFE isometric steady-state following active lengthening (2 s isometric at 90°, a 1 s lengthening phase at 40°/s, and 5 s at 130°). Motor evoked potentials (MEPs), cervicomedullary motor evoked potentials (CMEPs), and compound muscle action potentials (M-waves) were recorded from the tibialis anterior during the purely isometric contraction and RFE isometric steady-state. Results Compared to the purely isometric condition, following active lengthening, there was 10% RFE (p < 0.05), with a 17% decrease in normalized CMEP amplitude (CMEP/Mmax) (p < 0.05) and no change in normalized MEP amplitude (MEP/CMEP) (p > 0.05). Discussion These results indicate that spinal excitability is reduced during submaximal voluntary contractions in the RFE state with no change in supraspinal excitability. These findings may have further implications to everyday life offering insight into how the CNS optimizes control of skeletal muscle following submaximal active muscle lengthening.