A systematic review of how cannabinoids affect motoneuron output.

Spinal motoneurons contain many ion channels and receptors upon which various cannabinoids are known to act. This scoping review involved the synthesis of evidence from literature published before August 2022 about the effects of cannabinoids on quantifiable measures of motoneuron output. Four databases (MEDLINE, Embase, PsycINFO, and Web of Science CoreCollection) were queried and 4,237 unique articles were retrieved. Twenty-three studies met the inclusion criteria, and the findings from these studies were grouped according to four emergent themes: rhythmic motoneuron output, afferent feedback integration, membrane excitability, and neuromuscular junction transmission. This synthesis of evidence suggests that CB1 agonists can increase the frequency of cyclical patterns of motoneuron output (i.e., fictive locomotion). Furthermore, a majority of the evidence indicates that activating CB1 receptors at motoneuron synapses promotes excitation of motoneurons by enhancing excitatory synaptic transmission and depressing inhibitory synaptic transmission. The collated study results reveal variable effects of cannabinoids on acetylcholine release at the neuromuscular junction, and the influence of cannabinoids in this area requires more work to ensure precision of findings for CB1 agonist and antagonist impact. Altogether, these reports indicate that the endocannabinoid system is integral within the final common pathway and can impact motor output. This review contributes to understanding the effects of endocannabinoids on synaptic integration at the motoneuron and modulation of motor output.

On the horizon of aging and physical activity research.

This viewpoint is the result of a Horizon Round Table discussion of Exercise and Aging held during the 2017 Saltin International Graduate School in Exercise and Clinical Physiology in Gatineau, Quebec. This expert panel discussed key issues and approaches to future research into aging, across human physiological systems, current societal concerns, and funding approaches. Over the 60-min round table discussion, 3 major themes emerged that the panel considered to be "On the Horizon" of aging research. These themes include (i) aging is a process that extends from womb to tomb; (ii) the importance of longitudinal experimental studies; and (iii) the ongoing need to investigate multiple systems using an integrative approach between scientists, clinicians, and knowledge brokers. With a focus on these themes, we aim to identify critical questions, challenges, and opportunities that face scientists in advancing the understanding of exercise and aging.

The Task at Hand: Fatigue-Associated Changes in Cortical Excitability during Writing.

Measures of corticospinal excitability (CSE) made via transcranial magnetic stimulation (TMS) depend on the task performed during stimulation. Our purpose was to determine whether fatigue-induced changes in CSE made during a conventional laboratory task (isometric finger abduction) reflect the changes measured during a natural motor task (writing). We assessed single-and paired-pulse motor evoked potentials (MEPs) recorded from the first dorsal interosseous (FDI) of 19 participants before and after a fatigue protocol (submaximal isometric contractions) on two randomized days. The fatigue protocol was identical on the two days, but the tasks used to assess CSE before and after fatigue differed. Specifically, MEPs were evoked during a writing task on one day and during isometric finger abduction to a low-level target that matched muscle activation during writing on the other day. There was greater variability in MEP amplitude (F (1,18) = 13.55, p < 0.01) during writing compared to abduction. When participants were divided into groups according to writing style (printers, n = 8; cursive writers, n = 8), a task x fatigue x style interaction was revealed for intracortical facilitation (F (1,14) = 9.90, p < 0.01), which increased by 28% after fatigue in printers but did not change in cursive writers nor during the abduction task. This study is the first to assess CSE during hand-writing. Our finding that fatigue-induced changes in intracortical facilitation depend on the motor task used during TMS, highlights the need to consider the task-dependent nature of CSE when applying results to movement outside of the laboratory.

Estimates of persistent inward current in human motor neurons during postural sway.

Persistent inward current (PIC) plays a critical role in setting the gain of spinal motor neurons. In humans, most estimates of PIC are made from plantarflexor or dorsiflexor motor units in a seated position. This seated and static posture negates the task-dependent nature of the monoaminergic drive and afferent inhibition that modulate PIC activation. Our purpose was to estimate PIC during both the conventional seated posture and in a more functionally relevant anterior postural sway. We hypothesized that paired motor unit estimates of PIC would be greater when during standing compared with sitting. Soleus motor neuron PIC was estimated via the paired motor unit (PMU) technique. For each motor unit pair, difference in reference unit firing frequency (ΔF) estimates of PIC were made during isometric ramps in plantarflexion force during sitting (conventional approach) and during standing anterior postural sway (new approach). Baseline reciprocal inhibition (RI) was also measured in each posture using the poststimulus time histogram technique. ΔF estimates during standing postural sway were not different [2.64 ± 0.95 pulses/s (pps), P = 0.098] from seated PIC estimates (3.15 ± 1.45 pps) measured from the same motor unit pair. Similarly, reciprocal inhibition at the onset of each task was the same in standing (-0.60 ± 0.32, P = 0.301) and seated (-0.86 ± 0.82) postures. PMU recordings made during standing postural sway met all assumptions that underlay the PMU technique, including rate modulation ≥0.5 pps (3.11 ± 1.90 pps), rate-rate correlation r ≥ 0.7 (0.84 ± 0.13), and time between reference and test unit recruitment ≥1 s (1.83 ± 0.81 s). This study presents a novel, functionally relevant standing method for investigating PIC in humans.NEW & NOTEWORTHY Paired motor unit (PMU) estimates of persistent inward current (PIC) in human soleus motor units are typically made in seated posture. Our study demonstrates that these estimates can be made during standing forward sway, a task that more accurately reflects the postural role of human soleus muscle. PMU recordings made during standing postural sway were validated using all previously published criteria used to test the assumptions of the PMU technique. Standing estimates of PIC did not differ from seated estimates made from the same motor unit pairs.

Understanding exercise-dependent plasticity of motoneurons using intracellular and intramuscular approaches.

Spinal motoneurons (MN) exhibit exercise-dependent adaptations to increased activity, such as exercise and locomotion, as well as decreased activity associated with disuse, spinal cord injury, and aging. The development of several experimental approaches, in both human and animal models, has contributed significantly to our understanding of this plasticity. The purpose of this review is to summarize how intracellular recordings in an animal model and motor unit recordings in a human model have, together, contributed to our current understanding of exercise-dependent MN plasticity. These approaches and techniques will allow neuroscientists to continue to advance our understanding of MN physiology and the plasticity of the "final common path" of the motor system, and to design experiments to answer the critical questions that are emerging in this field.

Chronic exercise mitigates disease mechanisms and improves muscle function in myotonic dystrophy type 1 mice.

KEY POINTS: Myotonic dystrophy type 1 (DM1), the second most common muscular dystrophy and most prevalent adult form of muscular dystrophy, is characterized by muscle weakness, wasting and myotonia. A microsatellite repeat expansion mutation results in RNA toxicity and dysregulation of mRNA processing, which are the primary downstream causes of the disorder. Recent studies with DM1 participants demonstrate that exercise is safe, enjoyable and elicits benefits in muscle strength and function; however, the molecular mechanisms of exercise adaptation in DM1 are undefined. Our results demonstrate that 7 weeks of volitional running wheel exercise in a pre-clinical DM1 mouse model resulted in significantly improved motor performance, muscle strength and endurance, as well as reduced myotonia. At the cellular level, chronic physical activity attenuated RNA toxicity, liberated Muscleblind-like 1 protein from myonuclear foci and improved mRNA alternative splicing. ABSTRACT: Myotonic dystrophy type 1 (DM1) is a trinucleotide repeat expansion neuromuscular disorder that is most prominently characterized by skeletal muscle weakness, wasting and myotonia. Chronic physical activity is safe and satisfying, and can elicit functional benefits such as improved strength and endurance in DM1 patients, but the underlying cellular basis of exercise adaptation is undefined. Our purpose was to examine the mechanisms of exercise biology in DM1. Healthy, sedentary wild-type (SED-WT) mice, as well as sedentary human skeletal actin-long repeat animals, a murine model of DM1 myopathy (SED-DM1), and DM1 mice with volitional access to a running wheel for 7 weeks (EX-DM1), were utilized. Chronic exercise augmented strength and endurance in vivo and in situ in DM1 mice. These alterations coincided with normalized measures of myopathy, as well as increased mitochondrial content. Electromyography revealed a 70-85% decrease in the duration of myotonic discharges in muscles from EX-DM1 compared to SED-DM1 animals. The exercise-induced enhancements in muscle function corresponded at the molecular level with mitigated spliceopathy, specifically the processing of bridging integrator 1 and muscle-specific chloride channel (CLC-1) transcripts. CLC-1 protein content and sarcolemmal expression were lower in SED-DM1 versus SED-WT animals, but they were similar between SED-WT and EX-DM1 groups. Chronic exercise also attenuated RNA toxicity, as indicated by reduced (CUG)n foci-positive myonuclei and sequestered Muscleblind-like 1 (MBNL1). Our data indicate that chronic exercise-induced physiological improvements in DM1 occur in concert with mitigated primary downstream disease mechanisms, including RNA toxicity, MBNL1 loss-of-function, and alternative mRNA splicing.

On task: Considerations and future directions for studies of corticospinal excitability in exercise neuroscience and related disciplines.

Over the last few decades, transcranial magnetic stimulation (TMS) has emerged as a conventional laboratory technique in human neurophysiological research. Exercise neuroscientists have used TMS to study central nervous system contributions to fatigue, training, and performance in health, injury, and disease. In such studies, corticospinal excitability is often assessed at rest or during simple isometric tasks with the implication that the results may be extrapolated to more functional and complex movement outside of the laboratory. However, the neural mechanisms that influence corticospinal excitability are both state- and task-dependent. Furthermore, there are many sites of modulation along the pathway from the motor cortex to the muscle; a fact that is somewhat obscured by the all-encompassing and poorly defined term "corticospinal excitability". Therefore, the tasks we use to assess corticospinal excitability and the conclusions that we draw from such a global measure of the motor pathway must be taken into consideration. The overall objective of this review is to highlight the task-dependent nature of corticospinal excitability and the tools used to assess modulation at cortical and spinal sites of modulation. By weighing the advantages and constraints of conventional approaches to studying corticospinal excitability, and considering some new and novel approaches, we will continue to advance our understanding of the neural control of movement during exercise.

Cortical Mechanisms of Central Fatigue and Sense of Effort.

The purpose of this study was to investigate cortical mechanisms upstream to the corticospinal motor neuron that may be associated with central fatigue and sense of effort during and after a fatigue task. We used two different isometric finger abduction protocols to examine the effects of muscle activation and fatigue the right first dorsal interosseous (FDI) of 12 participants. One protocol was intended to assess the effects of muscle activation with minimal fatigue (control) and the other was intended to elicit central fatigue (fatigue). We hypothesized that high frequency repetitive transcranial magnetic stimulation (rTMS) of the supplementary motor area (SMA) would hasten recovery from central fatigue and offset a fatigue-induced increase in sense of effort by facilitating the primary motor cortex (M1). Constant force-sensation contractions were used to assess sense of effort associated with muscle contraction. Paired-pulse TMS was used to assess intracortical inhibition (ICI) and facilitation (ICF) in the active M1 and interhemispheric inhibitory (IHI) was assessed to determine if compensation occurs via the resting M1. These measures were made during and after the muscle contraction protocols. Corticospinal excitability progressively declined with fatigue in the active hemisphere. ICF increased at task failure and ICI was also reduced at task failure with no changes in IHI found. Although fatigue is associated with progressive reductions in corticospinal excitability, compensatory changes in inhibition and facilitation may act within, but not between hemispheres of the M1. rTMS of the SMA following fatigue enhanced recovery of maximal voluntary force and higher levels of ICF were associated with lower sense of effort following stimulation. rTMS of the SMA may have reduced the amount of upstream drive required to maintain motor output, thus contributing to a lower sense of effort and increased rate of recovery of maximal force.

Cortical hypoexcitability persists beyond the symptomatic phase of a concussion.

PRIMARY OBJECTIVE: The purpose of this research was to assess cortical excitability, voluntary activation of muscle and force sensation beyond the initial highly symptomatic period post-concussion (1-4 weeks post-injury). It was hypothesized that reduced excitability of the motor cortex may impair muscle activation and alter perceptions of force and effort. RESEARCH DESIGN: Eight concussed varsity football players were age- and position-matched with eight healthy teammates to control for training and body size. Healthy controls had not suffered a concussion in the previous 12 months. METHODS AND PROCEDURES: Paired-pulse transcranial magnetic stimulation was used to assess cortical excitability, voluntary activation was calculated using cortical twitch interpolation technique and sense of force was determined using constant-force sensation contractions. MAIN OUTCOMES AND RESULTS: The concussed group had lower intra-cortical facilitation (p = 0.036), lower maximal voluntary muscle activation (p = 0.038) and greater perceptions of force (p < 0.05), likely due to compensatory increases in upstream drive, than their healthy matched teammates. CONCLUSIONS: Taken together, these findings suggest a state of hypoexcitability that persists beyond the immediate acute phase of a concussion and may result in neuromuscular impairments that would call to question the athlete's readiness to return to sport.

Cortical mechanisms of mirror activation during maximal and submaximal finger contractions in Parkinson's disease.

BACKGROUND: Mirror movements are often reported in the early stages of Parkinson's disease (PD) and have been attributed to bilateral activation of the primary motor cortex; however, the precise cortical mechanisms are still unclear. Subclinical mirror activation (MA) that accompanies mirror movement has also been reported in healthy aging adults. OBJECTIVE: To characterize mirror activation and determine the cortical mechanisms of MA in individuals with PD who demonstrate mirror movements. HYPOTHESIS: 5 Hz rTMS to the supplementary motor area (SMA) will reduce MA by increasing interhemispheric inhibition (IHI) of the ipsilateral motor cortex. METHODS: MA was assessed using surface electromyography during maximal and submaximal unimanual contractions of the first dorsal interosseous in 7 individuals with PD with mirror movements (PD-MM: 70.9 ± 13.9 years; UPDRS III: 28.0 ± 8.2), 7 individuals with PD without mirror movements (PD-NM: 71 ± 10.1 years; UPDRS III: 27.8 ± 6.7) and 7 healthy controls (74.4 ± 6.0 years). IHI of the ipsilateral motor cortex was assessed using paired-pulse transcranial magnetic stimulation. RESULTS: MA was enhanced in both PD groups during submaximal contractions, with the latest onset of activation in PD-NM. Ipsilateral motor cortex excitability was the highest in PDMM; however, IHI did not differ between PD and controls. 5 Hz rTMS to the SMA reduced IHI in PD-NM; however, did not affect MA. CONCLUSIONS: IHI may not be the sole contributor to the expression of overt mirror movements in PD. Expression of overt mirror movement may be due to the combination of enhanced ipsilateral motor cortex excitability and an earlier onset of electromyographic activation in the mirror hand (mirror activation) in PDMM.

An evaluation of paired motor unit estimates of persistent inward current in human motoneurons.

Persistent inward current (PIC) plays an important role in setting the input-output gain of motoneurons. In humans, these currents are estimated by calculating the difference between synaptic input at motor unit recruitment and derecruitment (ΔF) derived from paired motor unit recordings. The primary objective of this study was to use the relationship between reciprocal inhibition (RI) and PIC to estimate the contribution of PIC relative to other motoneuron properties that result in nonlinear motor unit firing behavior. This study also assessed the contribution of other intrinsic properties (spike threshold accommodation and spike frequency adaptation) to ΔF estimates of PIC in human motor units by using ramps with varying rates of rise and duration. It was hypothesized that slower rates of ramp rise and longer ramp durations would inflate ΔF estimates of PIC, and RI and PIC values would only be correlated during the ramp with the fastest rate of rise and shortest duration when spike threshold accommodation and spike frequency adaptation is minimized. Fourteen university-aged participants took part in this study. Paired motor unit recordings were made from the right soleus muscle during ramp contractions of plantar flexors with three different rates of rise and durations. ΔF estimates of PIC increased with decreased rates of ramp rise (P < 0.01) and increased ramp durations (P < 0.01), most likely due to spike frequency adaptation. A correlation (r = 0.41; P < 0.03) between ΔF and RI provides evidence that PIC is the primary contributor to ΔF in shorter ramps with faster rates of rise.

Dynamic stability and steering control following a sport-induced concussion.

Loss of balance control is one of the cardinal symptoms following a concussion; however, the ability to detect the duration of these balance impairments seems to largely depend on task type and complexity. Typical balance assessment tools are simplistic and do not challenge dynamic balance control. Changing direction represents an internal perturbation that challenges the balance control system. The purpose of this study was to examine the effects of a concussion on dynamic stability and steering control. Nine male intercollegiate North American football players who experienced a concussion (CONC) were tested during the symptomatic phase (acute) and again once they had been cleared to return to play (RTP) while the controls (age- and position-matched teammates) were tested at a single time point coinciding with the acute phase testing of their matched injured player. All participants performed a steering task, requiring them to walk straight or turn in the direction of a visual cue located either 60° or 45° to the left or right of the centre line. CONC demonstrated increased swing time variability, segmental re-orientation variability, and the amount of time it took the centre of mass to reach the minimum lateral dynamic stability margin. These results suggest that CONC were more unstable and adopted a conservative gait strategy. Differences in the variability measures persisted even after the athlete was cleared to RTP. Overall, the findings reveal that intercollegiate football players with concussions have difficulty controlling temporal characteristics of gait, which cause dynamic instability to persist even at RTP.

Recovery of static stability following a concussion.

The purpose of this study was to use centre of pressure (COP) measurements to determine if static balance deficits had recovered when concussed athletes were cleared to return to play. Nine concussed varsity football players were matched with nine teammates who served as controls. Static balance in the anterior-posterior (A/P) and medial-lateral (M/L) directions was assessed during quiet stance with eyes open and eyes closed. Results showed that concussed football players displayed greater A/P COP displacements in the acute phase, which recovered by RTP; however, COP velocity remained elevated compared to controls even at RTP, particularly in the A/P direction. This balance control deficit in the A/P direction may suggest vestibular impairment, likely due to poor sensorimotor integration of the lateral vestibulospinal tract. The observed persistence of balance control deficits in concussed football players at RTP are usually undetected by traditional assessments because the current study used higher-order COP analysis. Future RTP balance measures may want to incorporate higher-order measures of balance.

Modulation of cortical excitability and interhemispheric inhibition prior to rhythmic unimanual contractions.

The objective of this study was to investigate premotor modulation of motor cortical excitability between rhythmic unimanual finger contractions. Applying TMS at rest prior to an anticipated contraction provides a measure of cortical excitability that reflects premotor modulatory drive and is uncontaminated by the alterations in spinal and cortical excitability that occur during muscle activation. We hypothesized that premotor structures contribute to unimanual movement through the modulation of intracortical and interhemispheric inhibitory circuits within the primary motor cortex and that this premotor modulation would be evident at rest between contractions. Thus, we used transcranial magnetic stimulation (TMS) to assess short interval intracortical inhibition (SICI) and interhemispheric inhibition (IHI) in a 500-ms epoch prior to a planned contraction of the right FDI in 10 participants (21.4±1.9 years). These measures of inhibition were made in three different states: (1) at complete rest (with no plan to contract), (2) at rest between rhythmic contractions, and (3) during low level contractions. Cortical excitability was enhanced prior to a contraction and during a contraction compared to at rest (F2,18=758.3, p<0.001). IHI was also increased prior to a contraction compared to at rest and during a contraction while SICI was only reduced during a contraction (F2,38=30.3, p<0.001).We used this pre-contraction protocol to investigate the cortical mechanisms of unimanual control. However, this protocol would be a useful tool to investigate any neuromuscular adaptation that may occur as a result of altered premotor modulation of cortical excitability, such as neuromuscular fatigue, training and movement disorders.

Whole-body hypothermia has central and peripheral influences on elbow flexor performance.

The superimposed twitch technique was used to study the effect of whole-body hypothermia on maximal voluntary activation of elbow flexors. Seven subjects [26.4 ± 4 years old (mean ± SD)] were exposed to 60 min of either immersion in 8°C water (hypothermia) or sitting in 22°C air (control). Voluntary activation was assessed during brief (3 s) maximal voluntary contractions (MVCs) and then during a 2 min fatiguing sustained MVC. Hypothermia (core temperature 34.8 ± 0.9°C) decreased maximal voluntary torque from 98.2 ± 1.0 to 82.8 ± 5.8% MVC (P < 0.001) and increased central conduction time from 7.9 ± 0.4 to 9.1 ± 0.7 ms (P < 0.05). Hypothermia also decreased maximal resting twitch amplitude from 17.6 ± 4.0 to 10.0 ± 1.7% MVC (P < 0.005) and increased the time-to-peak twitch tension from 55.4 ± 4.0 to 79.0 ± 11.7 ms (P < 0.001). During the 2 min contraction, hypothermia decreased initial torque (P < 0.01) but attenuated the subsequent rate of torque decline (control from 95.5 ± 4 to 29.4 ± 8% MVC; and hypothermia from 85.3 ± 8 to 37.3 ± 5% MVC; P < 0.01). Cortical superimposed twitches increased as fatigue developed but were always lower in the hypothermic conditions. Cortical superimposed twitches increased from a value of 0.4 ± 0.3% MVC prefatigue to 3.9 ± 1.4% MVC postfatigue (P < 0.001) in the hypothermic conditions and from 1.7 ± 0.9 to 5.5 ± 2.3% MVC in control conditions. Our results suggest that hypothermia decreases MVCs primarily via peripheral mechanisms and attenuates the rate of fatigue development by reducing central fatigue.

Caloric restriction does not offset age-associated changes in the biophysical properties of motoneurons.

Age-associated changes in neuromuscular function may be due to a loss of motor neurons as well as changes in their biophysical properties. Neuronal damage imposed by reactive oxygen species may contribute to age-related deficits in CNS function. Thus we hypothesized that aging would alter the functional properties of motoneurons and that caloric-restriction would offset these changes. Intracellular recordings were made from lumbar motoneurons of old Fisher Brown Norway (FBN) fed ad libitum (oldAL, 30.8+/-1.3 mo) or on a fortified calorie-restricted diet from 14 wk of age (oldCR, 31.0+/-1.8 mo). Basic and rhythmic firing properties recorded from these aged motoneurons (MNs) were compared with properties recorded from young FBN controls (young, 8.4+/-4.6 mo). Compared with young MNs, old MNs had a 104% greater (P<0.001) afterhyperpolarization potential (AHP), a 21.1% longer AHP half-decay time (P<0.05), 28.7% lower rheobase (P<0.001), 49.7% greater (P<0.001) input resistance, 21.1% (P<0.0001) less spike frequency adaptation, lower minimal (30.2%, P<0.0001) and maximal (16.7%, P<0.0001) steady-state firing frequencies, a lower (35.5%, P<0.0001) frequency-current slope, and an increased incidence of persistent inward current. Because basic properties became more diverse in old MNs and the slope of the frequency-current relationship, which is normally similar for high- and low-threshold MNs, was lower in the old group, we conclude that aging alters the biophysical properties of MNs in a fashion that cannot be simply attributed to a loss of high-threshold MNs. Surprisingly, caloric restriction, which is known to attenuate aging-associated changes in hindlimb muscles, had no effect on the progress of aging in the innervating MNs.

Does elimination of afferent input modify the changes in rat motoneurone properties that occur following chronic spinal cord transection?

The purpose of this study was to determine the effects of 6-8 weeks of chronic spinal cord isolation (SI, removal of descending, ascending and afferent inputs), compared with the same duration of spinal cord transection (ST, removal of descending input only) on hindlimb motoneurone biophysical properties. Adult female Sprague-Dawley rats were placed into three groups: (1) control (no removal of inputs), (2) ST and (3) SI. The electrophysiological properties from sciatic nerve motoneurones were recorded from deeply anaesthetized rats. Motoneurones in SI rats had significantly (P < 0.01) lower rheobase currents and higher spike afterhyperpolarization amplitudes and input resistances compared with motoneurones in control rats. A higher percentage (chi2, P = 0.01) of motoneurones in SI than control rats demonstrated frequency-current (f-I) relationships consistent with activation of persistent inward currents. Motoneurone steady state f-I slopes determined by increasing steps of 500 ms current pulses were significantly lower (P < 0.02) in SI than control rats. Motoneurone spike frequency adaptation measured using 30 s square-wave current injections (1.5-3.0 nA above the estimated rhythmic firing threshold), was similar for control and SI motoneurones. Changes in motoneurone properties following SI did not differ from ST. These findings indicate that the removal of afferent and ascending inputs along with descending inputs has little additional affect on motoneurone properties than removal of descending inputs alone. This study is the first to demonstrate that intact ascending and afferent input does not modify the effects of spinal transection on basic and rhythmic firing properties of rat hindlimb motoneurones.

Spike frequency adaptation of rat hindlimb motoneurons.

The objective of our study was to resolve two issues pertaining to motoneuron (MN) spike frequency adaptation (SFA): 1) to develop an index of SFA that is sensitive to a wide range of adaptation patterns and would correlate well with MN excitability and 2) to determine whether SFA pattern is stimulus current dependent. Sprague-Dawley rats (250-350 g) were anesthetized (ketamine-xylazine) before electrophysiological properties from sciatic nerve MNs located in the lumbar spinal cord were recorded. SFA was measured by 30-s square-wave current injections at 1.5, 3.0, and 5.0 nA above estimated rhythmic firing threshold. Discharges per second were significantly (P < 0.001) higher for 5-nA than for 1.5- and 3-nA currents > rhythmic firing threshold in the first 2 s. SFA was quantified by using ratios of the final to initial number of discharges with 1-, 2-, and 5-s bins. The best index of SFA was the percent decline in the number of spikes fired in the fifth 5-s bin relative to the first 5-s bin [1 - (bin 5/bin 1)]. With the use of this index, we found that SFA was significantly correlated with several measures of MN excitability, including estimated persistent inward current amplitude (r = -0.76) and rheobase current (r = 0.71), and tended to correlate with input resistance (r = -0.43) and frequency-current slope (r = -0.57). This index also showed the widest range of SFA among MNs. In conclusion, an SFA pattern can be ascertained for each MN and becomes more pronounced as MN excitability decreases. Finally, for the first time, we report evidence of a relationship between persistent inward current and SFA.

The influence of caffeine on voluntary muscle activation.

Caffeine is a very common CNS stimulant that has been of interest to physiologists because of its direct effects on skeletal muscle in vitro, as well as ergogenic effects on laboratory tests of human performance. While in vitro studies have clearly demonstrated the effects of the drug on the CNS, the effects of caffeine on the voluntary activation of muscle in humans are less defined. Voluntary as well as involuntary supraspinal input, alpha motor neuron membrane properties, and afferent feedback to spinal and supraspinal neurons all modulate voluntary muscle activation, and caffeine may therefore alter muscle activation at several sites along the motor pathway. This review explores the effects of caffeine on voluntary muscle activation that have been demonstrated in recent human studies and discusses the central mechanisms that may enhance activation. Evidence of caffeine's effects on the motor evoked potential, Hoffman reflex, self-sustained firing of the alpha motor neuron, and pain and force sensation are presented as well as limitations and considerations of using the drug in human neuromuscular studies.

Caffeine: a valuable tool to study central fatigue in humans?

This review focuses on caffeine's effects on the central modulation of muscle activation in humans. The drug's effects on voluntary muscle activation, the Hoffman reflex, motor-evoked potentials, self-sustained firing, pain, and sensation are discussed, and the possibility that caffeine maybe useful in the study of central fatigue is explored.