Excitatory drive to spinal motoneurones is necessary for serotonin to modulate motoneurone excitability via 5-HT2 receptors in humans.

Serotonin modulates corticospinal excitability, motoneurone firing rates and contractile strength via 5-HT2 receptors. However, the effects of these receptors on cortical and motoneurone excitability during voluntary contractions have not been explored in humans. Therefore, the purpose of this study was to investigate how 5-HT2 antagonism affects corticospinal and motoneuronal excitability with and without descending drive to motoneurones. Twelve individuals (aged 24 ± 4 years) participated in a double-blind, placebo-controlled, crossover study, whereby the 5-HT2 antagonist cyproheptadine was administered. Transcranial magnetic stimulation (TMS) was delivered to the motor cortex to produce motor evoked potentials (MEPs), and electrical stimulation at the cervicomedullary junction was used to generate cervicomedullary motor evoked potentials (CMEPs) in the biceps brachii at rest and during a range of submaximal elbow flexions. Evoked potentials were also obtained after a conditioning TMS pulse to produce conditioned MEPs and CMEPs (100 ms inter-stimulus interval). 5-HT2 antagonism reduced maximal torque (p < 0.001), and compared to placebo, reduced unconditioned MEP amplitude at rest (p = 0.003), conditioned MEP amplitude at rest (p = 0.033) and conditioned MEP amplitude during contractions (p = 0.020). 5-HT2 antagonism also increased unconditioned CMEP amplitude during voluntary contractions (p = 0.041) but not at rest. Although 5-HT2 antagonism increased long-interval intracortical inhibition, net corticospinal excitability was unaffected during voluntary contractions. Given that spinal motoneurone excitability was only affected when descending drive to motoneurones was present, the current study indicates that excitatory drive is necessary for 5-HT2 receptors to regulate motoneurone excitability but not intracortical circuits.

Can the cross-education of strength attenuate the impact of detraining after a period of strength training? A quasi-randomized trial.

PURPOSE: Unilateral strength training may attenuate the decline in muscle strength and size in homologous, contralateral muscles. This study aimed to determine whether the cross-education of strength could specifically attenuate the effects of detraining immediately after a short (prehabilitation-type) period of strength training. METHODS: Twenty-six strength-trained participants were assigned to either four weeks of unilateral strength training of the stronger arm (UNI) or detraining (Detrain). Motor evoked potential (MEP) and cortical silent period (cSP) responses, muscle cross-sectional area (CSAFlexor; peripheral quantitative computed tomography) and maximal strength, rate of force development (RFD) and muscle activation (EMG) were examined in both elbow flexors before and after the intervention period. RESULTS: In UNI, one-repetition maximum (1-RM) strength improved in both the trained (∆ = 2.0 ± 0.9 kg) and non-trained (∆ = 0.8 ± 0.9 kg) arms despite cessation of training of the weaker arm, whereas 1-RM strength was unchanged in Detrain. Maximal voluntary isometric contraction, isokinetic peak torque, and RFD did not change in either group. No neural changes were detected in UNI, but cSP increased in Detrain (∆ = 0.010 ± 0.015 s). CSAFlexor increased in the trained arm (∆ = 51 ± 43 mm2) but decreased in the non-trained arm (∆ = -53 ± 50 mm2) in UNI. CSAFlexor decreased in both arms in Detrain and at a similar rate to the non-trained arm in UNI. CONCLUSION: UNI attenuated the effects of detraining in the weaker arm as shown by the improvement in 1-RM strength. However, the cross-education of strength did not attenuate the decline in muscle size in the contralateral arm.

Corticospinal and intracortical responses from both motor cortices following unilateral concentric versus eccentric contractions.

Cross-education is the phenomenon where training of one limb can cause neuromuscular adaptations in the opposite untrained limb. This effect has been reported to be greater after eccentric (ECC) than concentric (CON) strength training; however, the underpinning neurophysiological mechanisms remain unclear. Thus, we compared responses to transcranial magnetic stimulation (TMS) in both motor cortices following single sessions of unilateral ECC and CON exercise of the elbow flexors. Fourteen healthy adults performed three sets of 10 ECC and CON right elbow flexor contractions at 75% of respective maximum on separate days. Elbow flexor maximal voluntary isometric contraction (MVIC) torques were measured before and after exercise, and responses to single- and paired-pulse TMS were recorded from the non-exercised left and exercised right biceps brachii. Pre-exercise and post-exercise responses for ECC and CON were compared by repeated measures analyses of variance (ANOVAs). MVIC torque of the exercised arm decreased (p < 0.01) after CON (-30 ± 14%) and ECC (-39 ± 13%) similarly. For the non-exercised left biceps brachii, resting motor threshold (RMT) decreased after CON only (-4.2 ± 3.9% of maximum stimulator output [MSO], p < 0.01), and intracortical facilitation (ICF) decreased (-15.2 ± 20.0%, p = 0.038) after ECC only. For the exercised right biceps, RMT increased after ECC (8.6 ± 6.2% MSO, p = 0.014) but not after CON (6.4 ± 8.1% MSO, p = 0.066). Thus, unilateral ECC and CON elbow flexor exercise modulated excitability differently for the non-exercised hemisphere. These findings suggest that responses after a single bout of exercise may not reflect longer term adaptations.

Effects of jaw clenching and mental stress on persistent inward currents estimated by two different methods.

Spinal motoneuron firing depends greatly on persistent inward currents (PICs), which in turn are facilitated by the neuromodulators serotonin and noradrenaline. The aim of this study was to determine whether jaw clenching (JC) and mental stress (MS), which may increase neuromodulator release, facilitate PICs in human motoneurons. The paired motor unit (MU) technique was used to estimate PIC contribution to motoneuron firing. Surface electromyograms were collected using a 32-channel matrix on gastrocnemius medialis (GM) during voluntary, ramp, plantar flexor contractions. MU discharges were identified, and delta frequency (ΔF), a measure of recruitment-derecruitment hysteresis, was calculated. Additionally, another technique was used (VibStim) that evokes involuntary contractions that persist after cessation of combined Achilles tendon vibration and triceps surae neuromuscular electrical stimulation. VibStim measures of plantar flexor torque and soleus activity may reflect PIC activation. ΔF was not significantly altered by JC (p = .679, n = 18, 9 females) or MS (p = .147, n = 14, 5 females). However, all VibStim variables quantifying involuntary torque and muscle activity during and after vibration cessation were significantly increased in JC (p < .011, n = 20, 10 females) and some, but not all, increased in MS (p = .017-.05, n = 19, 10 females). JC and MS significantly increased the magnitude of involuntary contractions (VibStim) but had no effect on GM ΔF during voluntary contractions. Effects of increased neuromodulator release on PIC contribution to motoneuron firing might differ between synergists or be context dependent. Based on these data, the background level of voluntary contraction and, hence, both neuromodulation and ionotropic inputs could influence neuromodulatory PIC enhancement.

Motor cortical excitability and pre-supplementary motor area neurochemistry in healthy adults with substantia nigra hyperechogenicity.

Substantia nigra (SN) hyperechogenicity, viewed with transcranial ultrasound, is a risk marker for Parkinson's disease. We hypothesized that SN hyperechogenicity in healthy adults aged 50-70 years is associated with reduced short-interval intracortical inhibition in primary motor cortex, and that the reduced intracortical inhibition is associated with neurochemical markers of activity in the pre-supplementary motor area (pre-SMA). Short-interval intracortical inhibition and intracortical facilitation in primary motor cortex was assessed with paired-pulse transcranial magnetic stimulation in 23 healthy adults with normal (n = 14; 61 ± 7 yrs) or abnormally enlarged (hyperechogenic; n = 9; 60 ± 6 yrs) area of SN echogenicity. Thirteen of these participants (7 SN- and 6 SN+) also underwent brain magnetic resonance spectroscopy to investigate pre-SMA neurochemistry. There was no relationship between area of SN echogenicity and short-interval intracortical inhibition in the ipsilateral primary motor cortex. There was a significant positive relationship, however, between area of echogenicity in the right SN and the magnitude of intracortical facilitation in the right (ipsilateral) primary motor cortex (p = .005; multivariate regression), evidenced by the amplitude of the conditioned motor evoked potential (MEP) at the 10-12 ms interstimulus interval. This relationship was not present on the left side. Pre-SMA glutamate did not predict primary motor cortex inhibition or facilitation. The results suggest that SN hyperechogenicity in healthy older adults may be associated with changes in excitability of motor cortical circuitry. The results advance understanding of brain changes in healthy older adults at risk of Parkinson's disease.

Sprint cycling rate of torque development associates with strength measurement in trained cyclists.

PURPOSE: A cyclist's rate of force/torque development (RFD/RTD) and peak force/torque can be measured during single-joint or whole-body isometric tests, or during cycling. However, there is limited understanding of the relationship between these measures, and of the mechanisms that contribute to each measure. Therefore, we examined the: (i) relationship between quadriceps central and peripheral neuromuscular function with RFD/RTD in isometric knee extension, isometric mid-thigh pull (IMTP), and sprint cycling; and (ii) relationship among RFD/RTD and peak force/torque between protocols. METHODS: Eighteen trained cyclists completed two familiarisation and two experimental sessions. Each session involved an isometric knee extension, IMTP, and sprint cycling protocol, where peak force/torque, average and peak RFD/RTD, and early (0-100 ms) and late (0-200 ms) RFD/RTD were measured. Additionally, measures of quadriceps central and peripheral neuromuscular function were assessed during the knee extension. RESULTS: Strong relationships were observed between quadriceps early EMG activity (EMG50/M) and knee extension RTD (r or ρ = 0.51-0.65) and IMTP late RFD (r = 0.51), and between cycling early or late RTD and peak twitch torque (r or ρ = 0.70-0.75). Strong-to-very strong relationships were observed between knee extension, IMTP, and sprint cycling for peak force/torque, early and late RFD/RTD, and peak RFD/RTD (r or ρ = 0.59-0.80). CONCLUSION: In trained cyclists, knee extension RTD or IMTP late RFD are related to measures of quadriceps central neuromuscular function, while cycling RTD is related to measures of quadriceps peripheral neuromuscular function. Further, the strong associations among force/torque measures between tasks indicate a level of transferability across tasks.

Differences in Trapezius Muscle H-Reflex between Asymptomatic Subjects and Symptomatic Shoulder Pain Subjects.

In chronic shoulder pain, adaptations in the nervous system such as in motoneuron excitability, could contribute to impairments in scapular muscles, perpetuation and recurrence of pain and reduced improvements during rehabilitation. The present cross-sectional study aims to compare trapezius neural excitability between symptomatic and asymptomatic subjects. In 12 participants with chronic shoulder pain (symptomatic group) and 12 without shoulder pain (asymptomatic group), the H reflex was evoked in all trapezius muscle parts, through C3/4 nerve stimulation, and the M-wave through accessory nerve stimulation. The current intensity to evoke the maximum H reflex, the latency and the maximum peak-to-peak amplitude of both the H reflex and M-wave, as well as the ratio between these two variables, were calculated. The percentage of responses was considered. Overall, M-waves were elicited in most participants, while the H reflex was elicited only in 58-75% or in 42-58% of the asymptomatic and symptomatic participants, respectively. A comparison between groups revealed that the symptomatic group presented a smaller maximum H reflex as a percentage of M-wave from upper trapezius and longer maximal H reflex latency from the lower trapezius (p < 0.05). Subjects with chronic shoulder pain present changes in trapezius H reflex parameters, highlighting the need to consider trapezius neuromuscular control in these individuals' rehabilitation.

Contraction Velocity of the Elbow Flexors Assessed by Tensiomyography: A Comparison Between Formulas.

ABSTRACT: Mesquita, RNO, Latella, C, Ruas, CV, Nosaka, K, and Taylor, JL. Contraction velocity of the elbow flexors assessed by tensiomyography: A comparison between formulas. J Strength Cond Res 37(10): 1969-1977, 2023-Muscle contraction velocity ( Vc ) assessed by tensiomyography is a promising measure for athlete profiling. Multiple formulas are used to estimate Vc , but the most suitable method is yet to be established. Fifteen adults (2 female subjects) underwent tensiomyography assessment of biceps brachii muscle at 10, 45 and 90° of elbow flexion on 2 separate days. Vc was calculated using 6 formulas. Formulas 1 and 2 are measures of the early phase of the twitch; Formulas 3-5 are measures over a wider time-window, with Formula 5 normalizing Vc to maximal displacement ( D m); and we proposed Formula 6 as a measure of peak Vc . Test-retest reliability, the required minimum number of trials, proportional bias, and effects of joint angle were investigated. Higher reliability (coefficient of variation: 2.8-6.9%) was found for Formula 1 (0-2 mm of displacement) and Formula 5 (normalized 10-90% of D m). Overall, a minimum of 6-7 trials was required to obtain reliable estimates. For 10° only, significant positive proportional bias ( r = 0.563-0.670) was found for all formulas except Formula 5. Vc was faster ( p < 0.001) at shorter muscle lengths for all formulas except Formula 5 ( p = 0.06). Vc in the early phase of the twitch was more reliable when calculated using absolute displacement (Formula 1) than a relative threshold (Formula 2). Over a larger time-window, Formulas 3 and 4 were similarly reliable. Because they are derived from different components of the twitch and different parameters, the different formulas should not be used interchangeably. Additionally, more precise nomenclature is required to describe the information obtained from each formula.

Voluntary activation of muscle in humans: does serotonergic neuromodulation matter?

Ionotropic inputs to motoneurones have the capacity to depolarise and hyperpolarise the motoneurone, whereas neuromodulatory inputs control the state of excitability of the motoneurone. Intracellular recordings of motoneurones from in vitro and in situ animal preparations have provided extraordinary insight into the mechanisms that underpin how neuromodulators regulate neuronal excitability. However, far fewer studies have attempted to translate the findings from cellular and molecular studies into a human model. In this review, we focus on the role that serotonin (5-HT) plays in muscle activation in humans. 5-HT is a potent regulator of neuronal firing rates, which can influence the force that can be generated by muscles during voluntary contractions. We firstly outline structural and functional characteristics of the serotonergic system, and then describe how motoneurone discharge can be facilitated and suppressed depending on the 5-HT receptor subtype that is activated. We then provide a narrative on how 5-HT effects can influence voluntary activation during muscle contractions in humans, and detail how 5-HT may be a mediator of exercise-induced fatigue that arises from the central nervous system.

Effects of reciprocal inhibition and whole-body relaxation on persistent inward currents estimated by two different methods.

Persistent inward currents (PICs) are crucial for initiation, acceleration, and maintenance of motoneuron firing. As PICs are highly sensitive to synaptic inhibition and facilitated by serotonin and noradrenaline, we hypothesised that both reciprocal inhibition (RI) induced by antagonist nerve stimulation and whole-body relaxation (WBR) would reduce PICs in humans. To test this, we estimated PICs using the well-established paired motor unit (MU) technique. High-density surface electromyograms were recorded from gastrocnemius medialis during voluntary, isometric 20-s ramp, plantarflexor contractions and decomposed into MU discharges to calculate delta frequency (ΔF). Moreover, another technique (VibStim), which evokes involuntary contractions proposed to result from PIC activation, was used. Plantarflexion torque and soleus activity were recorded during 33-s Achilles tendon vibration and simultaneous 20-Hz bouts of neuromuscular electrical stimulation (NMES) of triceps surae. ΔF was decreased by RI (n = 15, 5 females) and WBR (n = 15, 7 females). In VibStim, torque during vibration at the end of NMES and sustained post-vibration torque were reduced by WBR (n = 19, 10 females), while other variables remained unchanged. All VibStim variables remained unaltered in RI (n = 20, 10 females). Analysis of multiple human MUs in this study demonstrates the ability of local, focused inhibition to attenuate the effects of PICs on motoneuron output during voluntary motor control. Moreover, it shows the potential to reduce PICs through non-pharmacological, neuromodulatory interventions such as WBR. The absence of a consistent effect in VibStim might be explained by a floor effect resulting from low-magnitude involuntary torque combined with the negative effects of the interventions. KEY POINTS: Spinal motoneurons transmit signals to skeletal muscles to regulate their contraction. Motoneuron firing partly depends on their intrinsic properties such as the strength of persistent (long-lasting) inward currents (PICs) that make motoneurons more responsive to excitatory input. In this study, we demonstrate that both reciprocal inhibition onto motoneurons and whole-body relaxation reduce the contribution of PICs to human motoneuron firing. This was observed through analysis of the firing of single motor units during voluntary contractions. However, an alternative technique that involves tendon vibration and neuromuscular electrical stimulation to evoke involuntary contractions showed less effect. Thus, it remains unclear whether this alternative technique can be used to estimate PICs under all physiological conditions. These results improve our understanding of the mechanisms of PIC depression in human motoneurons. Potentially, non-pharmacological interventions such as electrical stimulation or relaxation could attenuate unwanted PIC-induced muscle contractions in conditions characterised by motoneuron hyperexcitability.

Enhanced availability of serotonin limits muscle activation during high-intensity, but not low-intensity, fatiguing contractions.

Serotonin (5-HT) modulates motoneuron excitability during muscle contractions, where the release of 5-HT in the central nervous system (CNS) is linked to the intensity of physical activity. Although there is evidence that enhanced availability of 5-HT can exacerbate fatigue, these effects on the development of fatigue during different contraction intensities are largely unknown. The purpose of this study was to investigate how enhanced 5-HT availability affects voluntary muscle activation and corticospinal excitability during fatigue-inducing contractions. Two experiments were performed. In the first experiment (n = 11), 12 isometric elbow flexions at 20% maximal voluntary contractions (MVCs) were performed for 2 min each with 40-s rest periods. In the second experiment (n = 14), 12 maximal isometric elbow flexions were held for 10 s each with 40-s rest periods. In both experiments, the selective serotonin reuptake inhibitor (20-mg paroxetine), or a placebo, was administered in a two-way crossover design. Muscle responses to transcranial magnetic stimulation (TMS) of the motor cortex (both experiments 1 and 2), as well as motor point stimulation of the elbow flexors (experiment 2) were assessed. Paroxetine reduced both motor cortical (P = 0.018) and motor point voluntary activation (P = 0.036) during the maximal contraction protocol. Paroxetine also reduced exercise-induced lengthening of the TMS silent period during the submaximal (P = 0.037) and maximal (P = 0.002) contraction protocols. Activation of inhibitory 5-HT1A receptors on motoneurons likely exacerbated exercise-induced reductions in voluntary drive to the elbow flexors. However, 5-HT modulation of motor activity also appeared at the supraspinal level.NEW & NOTEWORTHY As serotonin release onto motoneurons may be scaled to the strength of muscle contraction, it may have different effects when neuromuscular fatigue is induced by contractions of different intensities. Enhanced levels of serotonin compromised voluntary activation of muscle when fatigue was induced by strong contractions but not weak contractions. This provides evidence that the serotonergic system has the greatest influence on fatigue that is generated with high neural drive to the target muscle.

Effects of different modalities of afferent stimuli of the lumbo-sacral area on control of lumbar paravertebral muscles.

Somatosensory feedback to the central nervous system is essential to plan, perform and refine spine motor control. However, the influence of somatosensory afferent input from the trunk on the motor output to trunk muscles has received little attention. The objective was to compare the effects of distinct modalities of afferent stimulation on the net motoneuron and corticomotor excitability of paravertebral muscles. Fourteen individuals were recruited. Modulation of corticospinal excitability (motor-evoked potential [MEP]) of paravertebral muscles was measured when afferent stimuli (cutaneous noxious and non-noxious, muscle contraction) were delivered to the trunk at 10 intervals prior to transcranial magnetic stimulation. Each peripheral stimulation was applied alone, and subsequent electromyography (EMG) modulation was measured to control for net motoneuron excitability. MEP modulation and MEP/EMG ratio were used as measures of corticospinal excitability with and without control of net motoneuron excitability, respectively. MEP and EMG modulation were smaller after evoked muscle contraction than after cutaneous noxious and non-noxious stimuli. MEP/EMG ratio was not different between stimulation types. Both MEP and EMG amplitudes were reduced after evoked muscle contraction, but not when expressed as MEP/EMG ratio. Noxious and non-noxious stimulation had limited impact on all variables. Distinct modalities of peripheral afferent stimulation of the lumbo-sacral area differently modulated responses of paravertebral muscles, but without an influence on corticospinal excitability with control of net motoneuron excitability. Muscle stimulation reduced paravertebral activity and was best explained by spinal mechanisms. The impact of afferent stimulation on back muscles differs from the effects reported for limb muscles.

5-HT2 receptor antagonism reduces human motoneuron output to antidromic activation but not to stimulation of corticospinal axons.

The intrinsic electrical properties of motoneurons strongly affect motoneuron excitability to fast-acting excitatory ionotropic inputs. Serotonin (5-HT) is a neurochemical that alters the intrinsic properties of motoneurons, whereby animal models and in vitro experiments indicate that 5-HT increases motoneuron excitability by activating 5-HT2 receptors on the somato-dendritic compartment. In the current study, we examined how antagonism of the 5-HT2 receptor affects motoneuron excitability in humans. We hypothesised that motoneuron excitability would be reduced. The 5-HT2 antagonist cyproheptadine was administered to 10 healthy participants in a double-blinded, placebo-controlled, crossover trial. Electrical cervicomedullary stimulation was used to deliver a synchronised excitatory volley to motoneurons to elicit cervicomedullary motor evoked potentials (CMEPs) in the surface electromyography (EMG) signal of the resting biceps brachii. Likewise, electrical peripheral nerve stimulation was used to generate antidromic spikes in motoneurons and cause recurrent discharges, which were recorded with surface EMG as F-waves in a resting hand muscle. Compared with placebo, we found that 5-HT2 antagonism reduced the amplitude and persistence of F-waves but did not affect CMEP amplitude. 5-HT2 antagonism also reduced maximal contraction strength. The reduced recurrent discharge of motoneurons with 5-HT2 antagonism suggests that 5-HT2 receptors modulate the electrical properties of the initial segment or soma to promote excitability. Conversely, as cyproheptadine did not affect motoneuron excitability to brief synaptic input, but affected maximal contractions requiring sustained input, it seems likely that the 5-HT2 -mediated amplification of synaptic input at motoneuron dendrites is functionally significant only when excitatory input activates persistent inward currents.

The effect of acute intermittent hypoxia on human limb motoneurone output.

NEW FINDINGS: What is the central question of this study? Does a single session of repeated bouts of acute intermittent hypoxic breathing enhance the motoneuronal output of the limb muscles of healthy able-bodied participants? What is the main finding and its importance? Compared to breathing room air, there were some increases in motoneuronal output following acute intermittent hypoxia, but the increases were variable across participants and in time after the intervention and depended on which neurophysiological measure was checked. ABSTRACT: Acute intermittent hypoxia (AIH) induces persistent increases in output from rat phrenic motoneurones. Studies in people with spinal cord injury (SCI) suggest that AIH improves limb performance, perhaps via postsynaptic changes at cortico-motoneuronal synapses. We assessed whether limb motoneurone output in response to reflex and descending synaptic activation is facilitated after one session of AIH in healthy able-bodied volunteers. Fourteen participants completed two experimental days, with either AIH or a sham intervention (randomised crossover design). We measured H-reflex recruitment curves and homosynaptic post-activation depression (HPAD) of the H-reflex in soleus, and motor evoked potentials (MEPs) evoked by transcranial magnetic stimulation (TMS) and their recruitment curves in first dorsal interosseous. All measurements were performed at rest and occurred at baseline, 0, 20, 40 and 60 min post-intervention. The intervention was 30 min of either normoxia (sham, F i O 2 ${F_{{\rm{i}}{{\rm{O}}_{\rm{2}}}}}$  ≈ 0.21) or AIH (alternate 1-min hypoxia [ F i O 2 ${F_{{\rm{i}}{{\rm{O}}_{\rm{2}}}}}$  ≈ 0.09], 1-min normoxia). After AIH, the H-reflex recruitment curve shifted leftward. Lower stimulation intensities were needed to evoke 5%, 50% and 99% of the maximal H-reflex at 40 and 60 min after AIH (P < 0.04). The maximal H-reflex, recruitment slope and HPAD were unchanged after AIH. MEPs evoked by constant intensity TMS were larger 40 min after AIH (P = 0.027). There was no change in MEP recruitment or the maximal MEP. In conclusion, some measures of the evoked responses from limb motoneurones increased after a single AIH session, but only at discrete time points. It is unclear to what extent these changes alter functional performance.

Human corticospinal-motoneuronal output is reduced with 5-HT2 receptor antagonism.

Animal models indicate that serotonin (5-HT) release onto motoneurons facilitates motor output, particularly during strong motor activities. However, evidence for 5-HT effects during human movement are limited. This study examined how antagonism of the 5-HT2 receptor, which is a 5-HT receptor that promotes motoneuron excitability, affects human movement. Ten healthy participants (24.2 ± 1.9 yr) ingested 8 mg of cyproheptadine (competitive 5-HT2 antagonist) in a double-blinded, placebo-controlled, repeated-measures design. Transcranial magnetic stimulation (TMS) of the motor cortex was used to elicit motor evoked potentials (MEPs) from biceps brachii. First, stimulus-response curves (90%-160% active motor threshold) were obtained during very weak elbow flexions (10% of maximal). Second, to determine if 5-HT effects are scaled to the intensity of muscle contraction, TMS at a fixed intensity was applied during elbow flexions of 20%, 40%, 60%, 80%, and 100% of maximal. Cyproheptadine reduced the size of MEPs across the stimulus-response curves (P = 0.045). Notably, MEP amplitude was 22.3% smaller for the cyproheptadine condition for the strongest TMS intensity. In addition, cyproheptadine reduced maximal torque (P = 0.045), lengthened the biceps silent period during maximal elbow flexions (P = 0.037), and reduced superimposed twitch amplitude during moderate-intensity elbow flexions (P = 0.035). This study presents novel evidence that 5-HT2 receptors influence corticospinal-motoneuronal output, which was particularly evident when a large number of descending inputs to motoneurons were active. Although it is likely that antagonism of 5-HT2 receptors reduces motoneuron gain to ionotropic inputs, supraspinal mechanisms may have also contributed to the study findings.NEW & NOTEWORTHY Voluntary contractions and responses to magnetic stimulation of the motor cortex are dependent on serotonin activity in the central nervous system. 5-HT2 antagonism decreased evoked potential size to high-intensity stimulation, and reduced torque and lengthened inhibitory silent periods during maximal contractions. We provide novel evidence that 5-HT2 receptors are involved in muscle activation, where 5-HT effects are strongest when a large number of descending inputs activate motoneurons.

Involuntary sustained firing of plantar flexor motor neurones: effect of electrical stimulation parameters during tendon vibration.

PURPOSE: Simultaneous application of tendon vibration and neuromuscular electrical stimulation (NMES) induces an involuntary sustained torque. We examined the effect of different NMES parameters (intensity, pattern of stimulation and pulse width) on the magnitude of the evoked involuntary torque. METHODS: Plantar flexor torque was recorded during 33-s Achilles tendon vibration with simultaneous 20-Hz NMES bouts on triceps surae (n = 20; 13 women). Intensity was set to elicit 10, 20 or 30% of maximal voluntary contraction torque (MVC), pulse width was narrow (0.2 ms) or wide (1 ms), and the stimulus pattern varied (5 × 2-s or 10 × 1-s). Up to 12 different trials were performed in a randomized order, and then repeated in those who produced a sustained involuntary torque after the cessation of vibration. RESULTS: Six of 7 men and 5 of 13 women produced a post-vibration sustained torque. Eight of 20 participants did not complete the 30% trials, as they were perceived as painful. Torque during vibration at the end of NMES and the increase in torque throughout the trial were significantly higher in 20 than 10% trials (n = 11; 9.7 ± 9.0 vs 7.1 ± 6.1% MVC and 4.3 ± 4.5 vs 3.6 ± 3.5% MVC, respectively). Post-vibration sustained torque was higher in wide pulse-width trials (5.4 ± 5.9 vs 4.1 ± 4.3% MVC). Measures of involuntary torque were not different between 20 and 30% trials (n = 8). CONCLUSION: Bouts of 5 × 2-s NMES with wide pulse width eliciting 20% MVC provides the most robust responses and could be used to maximise the production of involuntary torque in triceps surae.

Enhanced serotonin availability amplifies fatigue perception and modulates the TMS-induced silent period during sustained low-intensity elbow flexions.

KEY POINTS: During maximal effort contractions, intense serotonin release via the raphe-spinal pathway spills over from the somato-dendritic compartment to activate inhibitory 5-HT1A receptors on the axon initial segment of motoneurons to reduce motoneuronal output. We investigated whether the same mechanism of central fatigue is present for low-intensity contractions, whereby weak serotonergic drive over an extended period may cause accumulation of serotonin and exacerbate central fatigue. Enhanced availability of serotonin did not directly influence motor pathways or motor performance during prolonged submaximal contraction. However, perceptions of muscle fatigue were greater, and the fatigue-induced lengthening of the silent period elicited via motor cortical stimulation was reduced with enhanced availability of serotonin. We propose that sustained low-intensity serotonergic neurotransmission influences supraspinal processes associated with fatigue, without directly influencing the output of the motor system during submaximal exercise. ABSTRACT: Enhanced availability of serotonin (5-HT) exacerbates central fatigue that occurs during maximal effort contractions. However, it is unknown if 5-HT release contributes to central fatigue during prolonged submaximal contractions. Hence, we assessed the effect that enhanced availability of 5-HT has on sustained low-intensity fatiguing contractions. Fifteen individuals (22.3 ± 2.1 years) ingested the 5-HT reuptake inhibitor paroxetine in a human, double-blinded, placebo-controlled, repeated-measures design. Participants performed a low-intensity isometric elbow flexion for 30 min (15% of maximal voluntary contraction, MVC). Throughout the protocol, brief MVCs were performed and muscle responses to transcranial magnetic stimulation (TMS) of the motor cortex, electrical stimulation of the brachial plexus, and motor point stimulation of the biceps were obtained. Ratings of perceived fatigue were also acquired. Paroxetine did not influence torque or voluntary activation during brief MVCs performed throughout the low-intensity contraction. However, paroxetine increased the perception of fatigue throughout the contraction (P = 0.005), and shortened the biceps silent period elicited via TMS during sustained submaximal contraction (P = 0.003) and brief MVCs (P = 0.011). Overall, it appears that prolonged low-intensity contractions do not cause intense 5-HT release onto motoneurons, and therefore, 5-HT does not activate inhibitory extra-synaptic 5-HT1A receptors of motoneurons to reduce their output. Although motor performance was unaffected by paroxetine, perceived fatigue was greater and intracortical inhibitory activity was reduced following the enhancement of endogenous concentrations of 5-HT during sustained submaximal contraction. Thus, 5-HT affects supraspinal processes during low-intensity contractions without directly altering motor pathways projecting to the muscle.

High-intensity, low-frequency repetitive transcranial magnetic stimulation enhances excitability of the human corticospinal pathway.

Paired corticospinal-motoneuronal stimulation (PCMS) is the repeated pairing of transcranial magnetic stimulation (TMS) with peripheral nerve stimulation to modify corticospinal synapses; however, it has yet to be determined whether PCMS modulates cortical excitability in a manner similar to paired-associative stimulation protocols. In this study, we first examined the effects of PCMS on adductor pollicis motor evoked potentials (MEPs). In experiment 1, on 2 separate days PCMS (repetitive, high-intensity TMS and ulnar nerve stimulation pairs; 1.5-ms interstimulus interval; 0.1 Hz) was compared with control conditioning of repetitive high-intensity TMS-only stimuli (0.1 Hz). Before and after conditioning, adductor pollicis MEPs were elicited using low-intensity TMS in three different coil orientations to preferentially activate corticospinal axons directly (thus bypassing cortical effects) or indirectly (cortical effects present). Unexpectedly, similar MEP increases were seen for all orientations on both PCMS (129 to 136% of baseline) and control days (108 to 129% of baseline). Given the common factor between conditioning protocols was repeated, high-intensity TMS, further experiments were performed to characterize this repetitive TMS (rTMS) protocol. In experiment 2, an intensity dependence of the rTMS protocol was revealed by a lack of change in MEPs elicited after repetitive low-intensity TMS (0.1 Hz; P = 0.37). In experiment 3, MEP recruitment curve and paired pulse analyses showed that the high-intensity rTMS protocol increased MEPs over a range of stimulus intensities but that effects were not accompanied by changes in intracortical inhibition or facilitation (P > 0.12). These experiments reveal a novel high-intensity, low-frequency rTMS protocol for enhancing corticospinal excitability.NEW & NOTEWORTHY In this study, we present a novel, intensity-dependent repetitive transcranial magnetic stimulation (rTMS) protocol that induces lasting, plastic changes within the corticospinal tract. High-intensity rTMS at a frequency of 0.1 Hz induces facilitation of motor evoked potentials (MEPs) lasting at least 35 min. Additionally, these changes are not limited only to small MEPs but occur throughout the recruitment curve. Finally, facilitation of MEPs following high-intensity rTMS does not appear to be due to changes in intracortical inhibition or facilitation.

A time-efficient method to determine parameters for measurement of short-interval intracortical inhibition for quadriceps.

Short-interval intracortical inhibition (SICI) is often assessed to investigate inhibitory responses in the primary motor cortex representation of the quadriceps. However, determining appropriate paired-pulse transcranial magnetic stimulation (TMS) parameters to optimise SICI measurement can be impractical and time-consuming. This study investigated the intensity required to elicit maximal and 50% of maximum inhibition, and the test-retest reliability of a time-efficient approach for SICI measurement in quadriceps. Nine men and six women (26.6 ± 4.4 years) underwent single and paired-pulse (3-ms interval) TMS during 10% maximal voluntary isometric contraction on two days. Responses were recorded from vastus lateralis (VL), rectus femoris (RF) and vastus medialis (VM). Test stimulus intensity was 140% of active motor threshold (AMT), and conditioning stimulus intensities (CSIs) ranged from 55% to 90% (eight intensities) of AMT (five test and five paired responses for each intensity). With CSI of 55% AMT, SICI was minimal (conditioned:test motor evoked potential [MEP]; 1.00, 0.96 and 0.95 for VL, RF and VM, respectively, <1.00 indicates inhibition). Inhibition was greater at 70%-90% AMT for VL (0.67-0.85), at 75%-90% AMT for RF (0.70-0.78) and at 80%-90% AMT for VM (0.59-0.68) when compared to 55% AMT. The CSIs that elicited maximal and 50% maximal inhibition were ~84% and ~75% AMT, respectively. Reliability for individual CSIs ranged from "poor-to-good" for all muscles. SICI averaged across all CSIs demonstrated "moderate" reliability for VL and VM, but "poor" reliability for RF. This method may offer a practical approach to individualise and select CSIs to investigate quadriceps inhibitory networks in neurophysiological studies.

Passive muscle stretching reduces estimates of persistent inward current strength in soleus motor units.

Prolonged (≥60 s) passive muscle stretching acutely reduces maximal force production at least partly through a suppression of efferent neural drive. The origin of this neural suppression has not been determined; however, some evidence suggests that reductions in the amplitude of persistent inward currents (PICs) in the motoneurons may be important. The aim of the present study was to determine whether acute passive (static) muscle stretching affects PIC strength in gastrocnemius medialis (GM) and soleus (SOL) motor units. We calculated the difference in instantaneous discharge rates at recruitment and de-recruitment (ΔF) for pairs of motor units in GM and SOL during triangular isometric plantar flexor contractions (20% maximum) both before and immediately after a 5 min control period and immediately after five 1 min passive plantar flexor stretches. After stretching, there was a significant reduction in SOL ΔF (-25.6%; 95% confidence interval, CI=-45.1% to -9.1%, P=0.002) but not GM ΔF These data suggest passive muscle stretching can reduce the intrinsic excitability, via PICs, of SOL motor units. These findings (1) suggest that PIC strength might be reduced after passive stretching, (2) are consistent with previously established post-stretch decreases in SOL but not GM EMG amplitude during contraction, and (3) indicate that reductions in PIC strength could underpin the stretch-induced force loss.