M-wave Amplitude Research Articles

Acute and delayed peripheral and central neuromuscular alterations induced by a short and intense downhill trail run.

Downhill sections are highly strenuous likely contributing to the development of neuromuscular fatigue in trail running. Our purpose was to investigate the consequences of an intense downhill trail run (DTR) on peripheral and central neuromuscular fatigue at knee extensors (KE) and plantar flexors (PF). Twenty-three runners performed a 6.5-km DTR (1264-m altitude drop) as fast as possible. The electromyographic activity of vastus lateralis (VL) and gastrocnemius lateralis (GL) was continuously recorded. Neuromuscular functions were assessed Pre-, Post-, and 2-day Post-DTR (Post2d). Maximal voluntary torques decreased Post (∼ -19% for KE, ∼ -25% for PF) and Post2d (∼ -9% for KE, ∼ -10% for PF). Both central and peripheral dysfunctions were observed. Decreased KE and PF voluntary activation (VA), evoked forces, VL M-wave amplitude, and KE low-frequency fatigue were observed at Post. Changes in VL M-wave amplitude were negatively correlated to VL activity during DTR. Changes in PF twitch force and VA were negatively correlated to GL activity during DTR. The acute KE VA deficit was about a third of that reported after ultramarathons, although peripheral alterations were similar. The prolonged force loss seems to be mainly associated to VA deficit likely induced by the delayed inflammatory response to DTR-induced ultrastructural muscle damage.

Wide-pulse-high-frequency neuromuscular electrical stimulation in cerebral palsy

ObjectiveThe present study assesses whether wide-pulse-high-frequency (WPHF) neuromuscular electrical stimulation (NMES) could result in extra-force production in cerebral palsy (CP) patients as previously observed in healthy individuals. MethodsTen CP and 10 age- and sex-matched control participants underwent plantar flexors NMES. Two to three 10-s WPHF (frequency: 100Hz, pulse duration: 1ms) and conventional (CONV, frequency 25Hz, pulse duration: 50μs) trains as well as two to three burst-like stimulation trains (2s at 25Hz, 2s at 100Hz, 2s at 25Hz; pulse duration: 1ms) were evoked. Resting soleus and gastrocnemii maximal H-reflex amplitude (Hmax) was normalized by maximal M-wave amplitude (Mmax) to quantify α-motoneuron modulation. ResultsSimilar Hmax/Mmax ratio was found in CP and control participants. Extra-force generation was observed both in CP (+18±74%) and control individuals (+94±124%) during WPHF (p<0.05). Similar extra-forces were found during burst-like stimulations in both groups (+108±110% in CP and +65±85% in controls, p>0.05). ConclusionAlthough the mechanisms underlying extra-force production may differ between WPHF and burst-like NMES, similar increases were observed in patients with CP and healthy controls. SignificanceDevelopment of extra-forces in response to WPHF NMES evoked at low stimulation intensity might open new possibilities in neuromuscular rehabilitation.

Spatial variation of compound muscle action potentials across human gastrocnemius medialis.

The massed action potential (M wave) elicited through nerve stimulation underpins a wide range of physiological and mechanical understanding of skeletal muscle structure and function. Although systematic approaches have evaluated the effect of different factors on M waves, the effect of the location and distribution of activated fibers within the muscle remains unknown. By detecting M waves from the medial gastrocnemius (MG) of 12 participants with a grid of 128 electrodes, we investigated whether different populations of muscle units have different spatial organization within MG. If populations of muscle units occupy discrete MG regions, current pulses of progressively greater intensities applied to the MG nerve branch would be expected to lead to local changes in M-wave amplitudes. Electrical pulses were therefore delivered at 2 pps, with the current pulse amplitude increased every 10 stimuli to elicit different degrees of muscle activation. The localization of MG response to increases in current intensity was determined from the spatial distribution of M-wave amplitude. Key results revealed that increases in M-wave amplitude were detected somewhat locally, by 10-50% of the 128 electrodes. Most importantly, the electrodes detecting greatest increases in M-wave amplitude were localized at different regions in the grid, with a tendency for greater stimulation intensities to elicit M waves in the more distal MG region. The presented results indicate that M waves recorded locally may not provide a representative MG response, with major implications for the estimation of, e.g., the maximal stimulation levels, the number of motor units, and the onset and normalization in H-reflex studies.

Depression of corticomotor excitability after muscle fatigue induced by electrical stimulation and voluntary contraction.

In this study, we examined the effect of muscle fatigue induced by tetanic electrical stimulation (ES) and submaximal isometric contraction on corticomotor excitability. Experiments were performed in a cross-over design. Motor-evoked potentials (MEPs) were elicited by transcranial magnetic stimulation (TMS). Corticomotor excitability was recorded before and after thumb opposition muscle fatigue tasks, in which 10% of the maximal tension intensity was induced by tetanic ES or voluntary contraction (VC). The participants were 10 healthy individuals who performed each task for 10 min. Surface electrodes placed over the abductor pollicis brevis (APB) muscle recorded MEPs. F- and M-waves were elicited from APB by supramaximal ES of the median nerve. After the tetanic ES- and VC tasks, MEP amplitudes were significantly lower than before the task. However, F- and M-wave amplitudes remained unchanged. These findings suggest that corticospinal excitability is reduced by muscle fatigue as a result of intracortical inhibitory mechanisms. Our results also suggest that corticomotor excitability is reduced by muscle fatigue caused by both VC and tetanic ES.

Delineating the Role of Cerebral Blood Flow and Hypocapnia on Neuromuscular Function

Neuromuscular fatigue, defined as the inability of a muscle to maintain a given level of force regardless of whether or not a task can be sustained, has been attributed, in part, to central mechanisms. Although reductions in cerebral blood flow (CBF) may be implicated in the development of central fatigue, the contribution from hypocapnic-reductions (i.e., PETCO2) in CBF versus reductions in CBF per se has yet to be isolated. PURPOSE: To examine the hypothesis that hypocapnia, independent of concomitant reductions in CBF, cause impairments in neuromuscular function. METHODS: Neuromuscular function, as indicated by motor evoked potentials (MEP), M-waves and cortical voluntary activation (cVA) of the flexor carpal radialis muscle during isometric wrist flexion, was assessed in 8 males (31±12 y) during 3 separate conditions: 1) cyclooxygenase inhibition using Indomethacin (Indo) to selectively reduce CBF; 2) controlled hyperventilation-induced hypocapnia (Hypocapnia); and 3) isocapnic hyperventilation (Isocapnia). CBF was estimated using transcranial Doppler ultrasound velocity measurements of the middle cerebral artery. Change from baseline and comparison of the 3 conditions was assessed using two-way repeated measures ANOVA. Relationships between variables were assessed using Pearson‘s correlations. RESULTS: The experimental conditions successfully isolated CBF and PETCO2. MEP amplitude (% M-wave amplitude) increased in hypocapnia (14.6±9.5%, p < 0.01) in comparison to Indo (-2.0±2.8%) and Isocapnia (0.6±1.8%); however, no significant changes were observed in M wave (p = 0.666) or cVA (p = 0.117). Correlation analysis revealed that MEP amplitude was inversely associated with PETCO2 (r = -0.54, p < 0.01) and cVA was weakly associated with CBF (r = 0.30, p < 0.05). CONCLUSIONS: Increased motor cortex excitability appears to be exclusive to hypocapnia but not reductions in CBF per se. However, a weak relationship between reductions in CBF and cVA exists, such that further research is required to confirm this finding and explore the potential implications. Supported by NSERC Discovery 227912-2012.

Peripheral And Central Fatigue Development And Short-term Recovery During All-out Repeated Sprints

Recent evidence suggests that power output during repeated sprints of short duration is adjusted by the central nervous system to restrain the development of locomotor muscle fatigue to a critical threshold. This adjustment of power output might involve a complex interplay between peripheral and central determinants of muscle fatigue. The rate of peripheral and/or central fatigue development and its influence on the pattern of power output during repeated sprints remain however largely unknown. PURPOSE:We aimed to determine the contribution of peripheral and central fatigue to power output reduction during repeated sprints and whether power output levels off when a critical threshold of peripheral fatigue is reached. METHODS: On separate days, twelve healthy subjects performed the following tests: 1, 4, 6, 8 and 10, 10 s all-out sprints, each with 30 s of passive recovery between sprints, as well as 8, 10 s sprints, each with 10 s of passive recovery to test the influence of varying the work / recovery ratio on our hypotheses. Peripheral fatigue was quantified via changes in pre- to post-exercise potentiated quadriceps twitch force evoked by supramaximal electrical stimulation of the femoral nerve (ΔQtw, 0.5 through 6 min recovery). Central fatigue was estimated via changes in pre- to post-exercise voluntary quadriceps activation (ΔVA). EMG during sprints was normalized by maximal M-wave amplitude (ΔRMS.Mmax-1). RESULTS: From the 1st to the 6th sprint, we found a significant and gradual reduction in ΔQtw (- 47 ± 3 %), ΔRMS.Mmax-1 (- 7 ± 1 %) and power output (- 25 ± 2 %). During the 4 subsequent sprints, no additional reduction of quadriceps fatigue, RMS.Mmax-1 or power output was found but VA was significantly reduced compared to baseline (- 11 ± 2 %). Recovery of Qtw, post-sprints (0.5 through 6 min), was reduced progressively following sprint #1 through #6, with no further reduction thereafter (through sprint #10). CONCLUSIONS: Both peripheral and central fatigue contribute to the reduction of power output during repeated sprints. The leveling off of power output and RMS.Max-1 when the same degree of peripheral fatigue was reached, independently of the work / recovery duration ratio, suggest that central motor drive was restricted to limit excessive development of peripheral muscle fatigue.

Effects of mechanical stimulation of sole support zones on the H-reflex characteristics under conditions of support unloading

The effects of mechanical stimulation of the sole support zones on the state of the m. soleus moto-neuron pool in humans have been studied under 7-day support unloading conditions, which were simulated using a dry immersion (DI) model. The excitability of the m. soleus motoneuron pool was estimated by the H-reflex amplitude normalized by the maximal M-wave amplitude before, during, and after immersion exposure. The results were compared for two groups of volunteers, i.e. a control group, which was subjected only to immersion exposure, and a test group, in which mechanical stimulation in locomotion regimens was applied daily during DI. The relative H-reflex amplitude increased during immersion in the control group, whereas such alterations were not detected in the test group.

M-wave potentiation after voluntary contractions of different durations and intensities in the tibialis anterior.

The study was undertaken to provide insight into the mechanisms underlying the potentiation of the muscle compound action potential (M wave) after conditioning contractions. M waves were evoked in the tibialis anterior before and after isometric maximal voluntary contractions (MVC) of 1, 3, 6, 10, 30, and 60 s, and after 3-s contractions at 10, 30, 50, 70, 90, and 100% MVC. The amplitude, duration, and area of the first and second phases of the M wave, together with the median frequency (Fmedian) and muscle fiber conduction velocity (MFCV) were recorded. Furthermore, twitch force, muscle fascicle length, and pennation angle were measured at rest, before, and 1 s after the conditioning contractions. The results indicate that only the amplitude of the second phase of the M wave was significantly increased after conditioning contractions. The extent of this potentiation was similar for MVC durations ranging from 1 to 10 s and augmented progressively with contraction intensity from 30 to 70% MVC. After these conditioning contractions, the duration and area of the two M-wave phases decreased (P < 0.05), whereas MFCV and Fmedian increased (P < 0.05). For all of these parameters, the greatest changes occurred 1 s after the conditioning contraction. Changes in MFCV after the contractions were correlated with those in M-wave second-phase amplitude (r(2) = 0.42; P < 0.05) and Fmedian (r(2) = 0.53; P < 0.05). In contrast, fascicle length and pennation angle did not change after the conditioning contractions. It is concluded that the potentiation of the second phase of the M wave is mainly due to an increased MFCV.

Neuromuscular fatigue following isometric contractions with similar torque time integral.

Torque time integral (TTI) is the combination of intensity and duration of a contraction. The aim of this study was to compare neuromuscular alterations following different isometric sub-maximal contractions of the knee extensor muscles but with similar TTI. Sixteen participants performed 3 sustained contractions at different intensities (25%, 50%, and 75% of Maximal Voluntary Contraction (MVC) torque) with different durations (68.5±33.4 s, 35.1±16.8 s and 24.8±12.9 s, respectively) but similar TTI value. MVC torque, maximal voluntary activation level (VAL), M-wave characteristics and potentiated doublet amplitude were assessed before and immediately after the sustained contractions. EMG activity of the vastus lateralis (VL) and -rectus femoris (RF) muscles was recorded during the sustained contractions. MVC torque reduction was similar in the 3 conditions after the exercise (-23.4±2.7%). VAL decreased significantly in a similar extent (-3.1±1.3%) after the 3 sustained contractions. Potentiated doublet amplitude was similarly reduced in the 3 conditions (-19.7±1.5%), but VL and RF M-wave amplitudes remained unchanged. EMG activity of VL and RF muscles increased in the same extent during the 3 contractions (VL: 54.5±40.4%; RF: 53.1±48.7%). These results suggest that central and peripheral alterations accounting for muscle fatigue are similar following isometric contractions with similar TTI. TTI should be considered in the exploration of muscle fatigue during sustained isometric contractions.

Biocompatible heterogeneous porous gel matrix NeuroGel(TM) promotes regeneration of rat sciatic nerve within tubular silicone prosthesis (experimental study).

The purpose of this study was to investigate the ability of NeuroGel™ to promote and enhance the regeneration of rat sciatic nerve within a 10-mm gap using silicone tubular prosthesis, and to evaluate and compare the regeneration outcomes versus autologous grafting. The 10-mm gap of rat sciatic nerve was bridged through silicone tubular prosthesis filled with dehydrated NeuroGel™, and NeuroGel™ saturated with rat NGF-B (NG30-NGG60, NGgfB30-NGgfB60). To assess the regeneration of the peripheral nerve we utilized three general and most commonly applied methods: electrophysiologic, hystomorphometric, and functional methods. The average M-wave amplitude (AMW index), or the intermediary index of the number of regenerated axons, in animal groups NGG60 and NGgfB60 60 days post-op was: 2.44 ± 0.57 mV and 1.87 ± 0.48 mV. These indices were statistically lower compared to the indices obtained after autologous grafting. The average impulse conduction velocity along motor fibers (VMF index), or the intermediary index of myelination rate, was: 13.3 mm/ms and 13.3 mm/ms, respectively, statistically equal to indices obtained after autologous grafting. The average density (D) of regenerated fibers (direct numerical indicator in contrast to intermediary AMW index) in animal groups NGG60 and NGgfB60 was: 4,920 ± 178.88 and 5,340 ± 150.33 per mm(2), respectively. These indices were statistically higher versus indices obtained after autologous grafting. Myelination rates of regenerated fibers in animal groups NGG60 and NGgfB60 were 73 and 86 %, respectively. They were also statistically higher. The average sciatic functional index (SFI) in NGG60 and NGgfB60 was: -25.57 ± 3.05 and -24.124 ± 4.8, respectively, which is statistically equal to indices obtained after autologous grafting. Neurogel™ strongly promotes the regeneration of rat sciatic nerve within silicone tubular prosthesis. After bridging a 10-mm gap through silicone prosthesis with Neurogel™ or Neurogel™ +NGF-B-modified intraluminal space, the myelination rate of regenerated axons of rat sciatic nerve appeared to be higher, and the axon count and functional recovery is similar to results seen with the autografting technique.

Exercise performance is regulated during repeated sprints to limit the development of peripheral fatigue beyond a critical threshold.

We hypothesized that exercise performance is adjusted during repeated sprints in order not to surpass a critical threshold of peripheral fatigue. Twelve men randomly performed three experimental sessions on different days, i.e. one single 10s all-out sprint and two trials of 10×10s all-out sprints with 30s of passive recovery in between. One trial was performed in the unfatigued state (CTRL) and one following electrically induced quadriceps muscle fatigue (FTNMES). Peripheral fatigue was quantified by comparing pre- with postexercise changes in potentiated quadriceps twitch force (ΔQtw-pot) evoked by supramaximal magnetic stimulation of the femoral nerve. Central fatigue was estimated by comparing pre- with postexercise voluntary activation of quadriceps motor units. The root mean square (RMS) of the vastus lateralis and vastus medialis EMG normalized to maximal M-wave amplitude (RMS.Mmax (-1)) was also calculated during sprints. Compared with CTRL condition, pre-existing quadriceps muscle fatigue in FTNMES (ΔQtw-pot=-29±4%) resulted in a significant (P<0.05) reduction in power output (-4.0±0.9%) associated with a reduction in RMS.Mmax (-1). However, ΔQtw-pot postsprints decreased by 51% in both conditions, indicating that the level of peripheral fatigue was identical and independent of the degree of pre-existing fatigue. Our findings show that power output and cycling EMG are adjusted during exercise in order to limit the development of peripheral fatigue beyond a constant threshold. We hypothesize that the contribution of peripheral fatigue to exercise limitation involves a reduction in central motor drive in addition to the impairment in muscular function.

Recovery of motor neuron excitability after facial nerve impairment in rats

Multiple studies have demonstrated alterations in excitability in the central nervous system after peripheral nerve injury. However, there are few reports on changes in the central nervous system after peripheral facial nerve injury. Our objective was to determine the excitability changes that occur in the facial nucleus after facial nerve impairment. The excitability changes in the facial nucleus were investigated by assessing two types of compound muscle action potentials (M and F waves) in the orbicularis oculi muscles, evoked by electrical stimulation of the zygomatic branch of the facial nerve. In rats, M and F waves were measured in the orbicularis oculi muscles before and every week up to 8 weeks after the application of nerve compression under anesthesia. M and F waves disappeared after nerve compression, only to reappear 2 weeks later, although M-wave amplitude was decreased and the latencies of both waves were delayed. Thereafter, these waves recovered gradually. During the recovery period, the F/M wave amplitude ratio, which is an indicator of facial nucleus excitability, significantly increased on the impaired side but not on the intact side. This increase was most prominent within 3 weeks; thereafter, the ratio gradually decreased and reached the levels recorded before facial nerve impairment by 7 weeks. Facial nerve impairment leads to hyperexcitability of the facial nucleus during the recovery period.

Age-related differences in rates of torque development and rise in EMG are eliminated by normalization

The purpose of this study was to compare the voluntary and evoked, absolute and normalized leg extension rates of torque development (RTD) and rates of rise in electromyography (RER) during commonly reported time intervals in young and old men. Fourteen young men (21.9±3.2years) and 16 older men (72.3±7.3years) completed three evoked and three voluntary isometric leg extension muscle actions to quantify absolute voluntary (peak, 30, 50, 100, and 200ms) and evoked (peak, 30, 50, and 100ms) RTD and RER. All RTD values were normalized (nRTD) to peak torque, while RER values were normalized (nRER) to peak-to-peak M-wave amplitude (MPP). Absolute voluntary RTDs and RERs were 58–122% and 70–76% greater (p≤0.05) for the young men, respectively. However, there were no age-related differences (p>0.05) for voluntary nRTDs, absolute and normalized evoked RTDs, or voluntary nRER. MPP and evoked RER and nRER were greater (p≤0.05) for the young men. In addition, voluntary RTD was more reliable in the young than the older men. Normalizing RTD to peak torque and RER to M-wave amplitude eliminated the age-related differences and suggested that the age-related declines in RTD and RER were a result of reduced muscle strength and M-wave amplitude, respectively. Therefore, our findings questioned the value of RTD and RER measurements in the various time intervals for explaining sarcopenia and suggested that maximal strength and M-wave amplitude may be sufficient.

The Effect of Creatine Loading on Neuromuscular Fatigue in Women

This study aimed to examine the effects of intermittent isometric fatigue on maximal voluntary contraction (MVC) strength, percent voluntary activation (%VA), peak twitch force (PTF), peak rate of force development (PRFD), half relaxation time (HRT), and maximal compound action potential (M-wave) amplitude of the soleus and medial gastrocnemius muscles before and after creatine (Cr) loading. Using a double-blinded, placebo-controlled, randomized design, 12 women were assigned to a Cr (n = 6; mean age ± SD = 23.3 ± 3.0 yr) or placebo (PL; n = 6; mean age ± SD = 21.3 ± 1.6 yr) group. Participants supplemented four times daily for 5 d with 5 g of Cr + 10 g of fructose or 10 g of fructose. At baseline and after testing, an isometric MVC and the twitch interpolation procedure were used before and after a 4-min isometric fatigue protocol of the plantarflexor muscles, which consisted of six intermittent duty cycles per minute (7-s contraction, 3-s relaxation) at 70% MVC. There were no interactions between the Cr and PL groups (P > 0.05) for any dependent variable. The fatigue protocol reduced voluntary strength (-17.8%, P < 0.001) and %VA (-3.7%, P = 0.005). Baseline PTF (P < 0.005) and PRFD (P < 0.001) values were less than those of all respective time points, but PTF value decreased from 3 min to 4 min and after testing (P < 0.005). HRT increased from baseline to minutes 1 and 2 and then returned to baseline at minutes 3 and 4 and after testing. The M-wave did not change (P > 0.05). Five days of Cr loading did not influence isometric force, %VA, evoked twitch properties, or the central and peripheral aspects of fatigue measured in this study.

Changes in Voluntary Activation Assessed by Transcranial Magnetic Stimulation during Prolonged Cycling Exercise

Maximal central motor drive is known to decrease during prolonged exercise although it remains to be determined whether a supraspinal deficit exists, and if so, when it appears. The purpose of this study was to evaluate corticospinal excitability and muscle voluntary activation before, during and after a 4-h cycling exercise. Ten healthy subjects performed three 80-min bouts on an ergocycle at 45% of their maximal aerobic power. Before exercise and immediately after each bout, neuromuscular function was evaluated in the quadriceps femoris muscles under isometric conditions. Transcranial magnetic stimulation was used to assess voluntary activation at the cortical level (VATMS), corticospinal excitability via motor-evoked potential (MEP) and intracortical inhibition by cortical silent period (CSP). Electrical stimulation of the femoral nerve was used to measure voluntary activation at the peripheral level (VAFNES) and muscle contractile properties. Maximal voluntary force was significantly reduced after the first bout (13±9%, P<0.01) and was further decreased (25±11%, P<0.001) at the end of exercise. CSP remained unchanged throughout the protocol. Rectus femoris and vastus lateralis but not vastus medialis MEP normalized to maximal M-wave amplitude significantly increased during cycling. Finally, significant decreases in both VATMS and VAFNES (∼8%, P<0.05 and ∼14%, P<0.001 post-exercise, respectively) were observed. In conclusion, reductions in VAFNES after a prolonged cycling exercise are partly explained by a deficit at the cortical level accompanied by increased corticospinal excitability and unchanged intracortical inhibition. When comparing the present results with the literature, this study highlights that changes at the cortical and/or motoneuronal levels depend not only on the type of exercise (single-joint vs. whole-body) but also on exercise intensity and/or duration.

Neural and muscular mechanisms of electrically induced fatigue in patients with spinal cord injury

Intervention study. The present study aimed at examining whether spinal and/or peripheral alterations are in the origin of neuromuscular fatigue development induced by intermittent neuromuscular electrical stimulation (NMES) in subjects with complete spinal cord injury (SCI). Neurological Rehabilitation Center CMN Propara, Montpellier, France. Thirteen volunteers with complete SCI participated in the study. The right triceps surae muscle was fatigued using a 30-Hz NMES protocol (2 s ON-2 s OFF) composed of three series of five trains. Spinal excitability (assessed by the H-reflex), muscle excitability (assessed by the M-wave), muscle contractile properties (assessed by mechanical response parameters) and torque evoked by NMES were tested before and after each five-train series. NMES-evoked torque significantly decreased throughout the protocol (P<0.001). This decrease was accompanied by a significant increase in M-wave amplitude (P<0.001), whereas H-reflex and the Hmax/Mmax ratio were not significantly modified. The amplitude of the mechanical response was significantly decreased at the end of the protocol (P<0.05). The results indicate significant fatigue development, which was attributed to impaired cross-bridge force-generating capacity, without modification of spinal excitability nor muscle excitability.

The effect of muscle fatigue on stimulus intensity requirements for central and peripheral fatigue quantification

The present study was designed to determine the stimulation intensity necessary for an adequate assessment of central and peripheral components of neuromuscular fatigue of the knee extensors. Three different stimulation intensities (100, 120 and 150% of the lowest intensity evoking a plateau in M-waves and twitch amplitudes, optimal stimulation intensity, OSI) were used to assess voluntary activation level (VAL) as well as M-wave, twitch and doublet amplitudes before, during and after an incremental isometric exercise performed by 14 (8 men) healthy and physically active volunteers. A visual analog scale was used to evaluate the associated discomfort. There was no difference (p > 0.05) in VAL between the three intensities before and after exercise. However, we found that stimulating at 100% OSI may overestimate the extent of peripheral fatigue during exercise, whereas 150% OSI stimulations led to greater discomfort associated with doublet stimulations as well as to an increased antagonist co-activation compared to 100% OSI. We recommend using 120% OSI, as it constitutes a good trade-off between discomfort and reliable measurements.

Abstract A269: A selective Aurora A inhibitor, TAS-119, enhanced the antitumor activity of taxanes in an intermittent dosing schedule without affecting neurotoxicity.

Abstract Background: Aurora A is a serine/threonine kinase that plays important roles in the regulation of the M phase of the mammalian cell cycle. Aberrant expression of Aurora A has been associated with spindle checkpoint dysfunction and increased resistance to the microtubule-polymerizing agents, paclitaxel and docetaxel (1). Moreover, Aurora A overexpression/ gene amplification has been reported in various types of human cancers. Previously, we have reported on the development of a highly potent and selective Aurora A inhibitor, TAS-119 (TAS-2104), which enhanced anti-proliferation activity by taxanes (2). This study was undertaken to select the optimal combination schedule of TAS-119 and taxanes both in vitro and in vivo. Additionally, we evaluated the effects of TAS-119 on peripheral neurotoxicity, a well known major toxicity of taxanes. Materials and Methods: For in vitro experiments, cells were exposed to paclitaxel and/or the Aurora A inhibitor in different order and duration. Cell viability was determined by measuring cellular ATP concentration. For an in vivo tumor efficacy study, human tumor cell lines were subcutaneously transplanted into the side flank of nude mice or rats. Dosing of taxanes and TAS-119 was started when the transplanted tumor size reached &amp;gt; ∼ 200 mm3. Peripheral neurotoxicity was evaluated in rats. Paclitaxel was dosed weekly for 8 weeks and neurotoxicity was assayed by changes of action potential (M-wave amplitude) after electrical stimuli or histopathology changes in nerve neurons. Results: In in vitro experiments, the Aurora A inhibitor enhanced paclitaxel activity in all 3 schedules tested; Aurora A inhibitor before or after paclitaxel or simultaneous treatment. However, the latter 2 schedules were better than first schedule. When different treatment duration times of the Aurora A inhibitor combined with a single dose of paclitaxel were tested, 48 hrs was found to be enough to cause maximum enhancement. Similar experiments were performed in in vivo xenograft models. Maximum enhancement by TAS-119 was observed with 2 to 4 days of treatment (dependent on the model). Moreover, the combination of TAS-119 did not exacerbate the paclitaxel-induced peripheral neurotoxicity in rats. Conclusion: In this study, intermittent dosing of TAS-119 is efficacious for combination with taxanes, and sustained exposure of TAS-119 is not required for maximal combination efficacy. These findings provide a rationale for the clinical evaluation of combination therapies of TAS-119 with taxanes under the defined optimal schedule. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A269. Citation Format: Keiko Ishihara, Hiroshi Sootome, Takamasa Suzuki, Norio Masuko, Akihiro Miura, Megumu Okada, Nobuyuki Oda, Hiroshi Hirai, Teruhiro Utsugi. A selective Aurora A inhibitor, TAS-119, enhanced the antitumor activity of taxanes in an intermittent dosing schedule without affecting neurotoxicity. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A269.

Twitch and M‐wave potentiation induced by intermittent maximal voluntary quadriceps contractions: Differences between direct quadriceps and femoral nerve stimulation

The aim of this study was to investigate differences in twitch and M-wave potentiation in the quadriceps femoris when electrical stimulation is applied over the quadriceps muscle belly versus the femoral nerve trunk. M-waves and mechanical twitches were evoked using direct quadriceps muscle and femoral nerve stimulation between 48 successive isometric maximal voluntary contractions (MVC) from 10 young, healthy subjects. Potentiation was investigated by analyzing the changes in M-wave amplitude recorded from the vastus medialis (VM) and vastus lateralis (VL) muscles and in quadriceps peak twitch force. Potentiation of twitch, VM M-wave, and VL M-wave were greater for femoral nerve than for direct quadriceps stimulation (P < 0.05). Despite a 50% decrease in MVC force, the amplitude of the M-waves increased significantly during exercise. In addition to enhanced electrogenic Na(+) -K(+) pumping, other factors (such as synchronization in activation of muscle fibers and muscle architectural properties) may significantly influence the magnitude of M-wave enlargement.

Voluntary muscle and motor cortical activation during progressive exercise and passively induced hyperthermia

This study examined whether central fatigue was exacerbated by an increase in muscle contractile speed caused by passive hyperthermia (PaH) and whether exercise-induced hyperthermia (ExH) combined with related peripheral fatigue influenced this response. The ExH was induced by cycling at 60% of maximal oxygen uptake in 38°C conditions and the PaH by sitting in a 48°C climate chamber. Ten men performed brief (≈ 5 s) and sustained (30 s) maximal voluntary isometric contractions (MVCs) of the knee extensors at baseline (CON, ∼37.1°C) and during moderate (MOD, ≈ 38.5°C) and severe (SEV, ∼39.5°C) hyperthermia. Motor nerve and transcranial magnetic stimulation were used to assess voluntary muscle and cortical activation level, along with contractile properties. Brief MVC force decreased to a similar extent during SEV-ExH (-8%) and SEV-PaH (-6%; P < 0.05 versus CON). Sustained MVC force also decreased during MOD-ExH (-10%), SEV-ExH (-13%) and SEV-PaH (-7%; P < 0.01 versus CON). Motor nerve and cortical activation were reduced on reaching MOD (≈ 3%) and SEV (≈ 5%) ExH and PaH during the brief and sustained MVCs (P < 0.01 versus CON). Peak twitch force decreased on reaching SEV-ExH and SEV-PaH (P < 0.05 versus CON). Following transcranial magnetic stimulation, during the brief and sustained MVCs the peak muscle relaxation rate increased in ExH and PaH (P < 0.01 versus CON). The increase was greatest during the sustained contraction in SEV-PaH (P < 0.01), but this did not exacerbate central fatigue relative to ExH. These results indicate that during fatiguing cycling exercise in the heat, quadriceps peak relaxation rate increases. However, the centrally mediated rate of activation appears sufficient to overcome even the largest increase in muscle relaxation rate, seen during SEV-PaH.